Cortisol, our body’s main stress hormone, has an amazing reach. Given the effects it has on our metabolism, inflammation, blood pressure, blood sugar, energy production and even the sleep-wake cycle, it’s no surprise that researchers early on latched onto signs of cortisol problems in chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM). Even after concluding that low cortisol levels (hypocortisolism) are common (but not universal) in ME/CFS and FM, they have never let go of the subject. Decades after low cortisol levels were first found in the disease, they’re still investigating the role cortisol plays in ME/CFS and FM.
A large, but flawed, recent study brought cortisol and hydrocortisone (the drug used to boost cortisol levels) to the fore. The results suggested that using low-dose hydrocortisone to reduce flares was safe and effective in both diseases and provided an opportunity to dig a bit deeper and check out what past studies have found and what some ME/CFS experts have said.
Sternberg, the senior author of the paper, reported that when activated by stress, the HPA axis creates a time-delayed, 6-fold+ increased surge of hydrocortisone (cortisol) surge in the blood, which in about 4 hours terminates the inflammatory bout. As the HPA axis weakens and cortisol production declines, though, because of age, injury, and/or heredity, a short- term, beneficial inflammatory response can turn into chronic inflammation. Sternberg asserted that hydrocortisone is the only substance produced by the body which can effectively terminate chronic states of inflammation.
When given in too large of amounts for extended periods of time, though, hydrocortisone administration could produce adverse effects. The authors repeatedly cited a 1957 paper, “DIAGNOSIS, TREATMENT AND PREVENTION OF CHRONIC HYPERCORTISONISM IN PATIENTS WITH RHEUMATOID ARTHRITIS* (psu.edu)“, which stated that too much hydrocortisone produces symptoms such as “excessive appetite, weight gain, euphoria, insomnia, increased nervous tension and irritability, facial rounding, increase of fat pads, fluid retention, edema, irregular menses, acne and excessive hair growth.
First the participants were given a food sensitivity test (not identified) and they monitored their symptoms for a week to establish a baseline. They also eliminated foods the laboratory test suggested were giving them problems.
Next came a 2-4 week induction period in which daily doses of hydrocortisone tablets sufficient to achieve a “minimum symptom” state (75% reduction in symptoms) were taken once a day from 7-9 am.
The participants ingested an average of 12 mg hydrocortisone per day – which the authors asserted was less than the 15 mg hydrocortisone given per day which produces adverse effects in the most sensitive adults. The 15 mg dose rate was based on the 1957 study ”
Dose During Induction Period
|Body mass||Week 1||Week 2||Week 3|
|<68 kg||60 mg/day||40 mg/day||20 mg/day|
|68 to 114 kg||80||60||40|
Approximately 15% of the participants failed to receive any significant benefits and were eliminated from the study.
Those participants who failed to achieve a 75% reduction in symptoms, but did improve otherwise, repeated the induction period and were given a broad spectrum antibiotic called doxycycline for approximately six weeks.
Stress management techniques (not identified) were provided to reduce symptoms flares.
After the induction period, the hydrocortisone protocol was discontinued until a flare hit at which point the participants went on a 5-day “flare-quenching regimen” which consisted of taking a hydrocortisone tablet immediately and then from 7-9 am for the next four days at the following doses.
Dose for the 5-day flare-quenching regimen
|Body mass||Day 1||Day 2||Day 3||Day 4||Day 5|
|<68 kg||30 mg||20 mg||20 mg||20 mg||10 mg|
|68 – 114 kg||40||30||20||20||10|
The patients were told to limit their “hydrocortisone booster use” to four times a month. This apparently meant 4 5-day flare-quenching hydrocortisone regimens a month – leaving, at the very least, 8-11 hydrocortisone holidays – which the authors asserted was enough avoid adrenal suppression. Those 8-11 days were enough “exercise” they felt for the adrenal gland to maintain health and stop producing cortisol. Patients who had trouble judging the beginning of a flare could, they felt, take hydrocortisone during the week and not on the weekends.
If the patients experienced significant symptom improvements “during days in which no hydrocortisone was ingested (that is, when they were on a “hydrocortisone holiday”), a hydrocortisone blood test was done. If their blood hydrocortisone levels were “significantly below average” (no levels provided) they were given extra hydrocortisone.
If evidence of too much hydrocortisone appeared (moon face and a hyper state), the patient’s dosage was assessed and the “appropriate action” was taken.
The patients rated their symptoms using a 0-10 scale (not defined).
No less than 2,428 participants with over 30 diseases enrolled in the study. Eighty-one physicians from 20 states participated. With 601 participants in the trial, fibromyalgia was the most common disease assessed. Twenty-five people with ME/CFS also participated. Arthritis and chronic pain diseases were common. A mishmash of other diseases ranging from Parkinson’s to dementia, to multiple sclerosis, and asthma, were also included.
Seventeen percent (n=413) of the participants did not improve, and 2,015 participants completed the study.
For those who completed the trial, the authors reported an average symptom improvement rate of 76%. The authors reported that the fibromyalgia and chronic fatigue syndrome patients had a 77% and 78% symptom improvement rate, respectively.
Remarkably – give the size of the study – no significant adverse reactions (weight gain, hypertension, gastrointestinal symptoms, insomnia, muscle pain or spasms, and hyperglycemia) were reported.
A 3-month, 56-person, 1998 randomized, placebo-controlled, double-blinded CFS trial used hydrocortisone (13 mg/m2 of body surface area every morning and 3 mg/m2 every afternoon (approx. 25-35 mg/day). Although Wellness scores significantly improved in those taking the drug relative to placebo, about 20% of the participants showed signs of adrenal suppression.
A 1-month, 32-person, 1999 randomized, crossover hydrocortisone trial found that low doses (5-10 mg) moderately reduced fatigue and resulted in almost 30% of the participants meeting normal fatigue scores. The authors concluded: “In some patients with chronic fatigue syndrome, low-dose hydrocortisone reduces fatigue levels in the short term.”
Another 1-month, 32-person, 2001 double-blind, placebo-controlled crossover hydrocortisone trial produced the expected increase in urinary cortisol output. In most patients, the increase in cortisol did not impact symptoms, but in about a quarter, it produced a reduction in fatigue “to normal population levels“. Giving cortisol to those patients also resolved “a blunted response to a corticotropin-releasing hormone (CRH) challenge. The authors concluded that the low dose did not result in adrenal suppression.
Dr. Myhill pointed out that the results were complicated by the fact that baseline cortisol levels did not predict who benefitted from the treatment, and that baseline levels were within normal reference ranges.
ME/CFS/FM Practitioners on Hydrocortisone
In 2008, WebMD reported that Kent Holtorf MD routinely treats patients with 5-15 mg hydrocortisone.
Fibromyalgia researcher Lesley Arnold, MD, disagreed with that approach stating:
“The evidence in favor of using steroids to treat these conditions just isn’t there. We just don’t have enough consistent data about abnormalities in the HPA axis.” and that some FM patients have increased and others decreased HPA axis functioning.
Dr. Teitelbaum believes that adrenal fatigue plays a major role in ME/CFS/FM and regularly uses ultra-low (<15 mg/day) doses of bioidentical hormones. In the latest edition of “From Fatigued to Fantastic“, Teitelbaum says it often makes ME/CFS/FM patients quickly feel better. Teitelbaum says he usually goes by symptoms but that a fasting cortisol of under 14 mcg/dL, especially if ACTH is under 25 pg/mL or glycosylated hemoglobin is 5.2 or less, suggests a trial of 5-15 mg hydrocortisone is warranted.
He asserts that the fears of using the hormone date back to the early days of hormone usage when doctors, not knowing any better, vastly overdosed their patients, causing some of them to die. His patients usually take it all in the morning or about 2/3rds in the morning, and the rest around lunch.
Dr. Myhill appears to be moving more to pregnenolone but does prescribe low dose hydrocortisone (5-10 mg) in patients for whom the Adrenal Stress Profile test shows a reduction in cortisol. She states:
“The use of hydrocortisone allows the adrenal gland to rest a little and, in time, resume normal production, at which point the hydrocortisone can be stopped. This removal of the hydrocortisone support should only happen once the patient feels considerably better, which may take several months or even years.”
Dr. Myhill prescribes cortisol “only in patients with a proven deficiency”. She uses 5-10 mg (rarely 15 mg) to be taken either in the morning, or morning and lunchtime. At that low of a dose, she reports that cortisol levels do not need to be monitored.
Other Possible Ways of Normalizing Cortisol Levels
The evidence that behavioral modifications such as mindfulness based stress reduction (MBSR) can normalize cortisol levels is mixed, with some studies finding so and others not. A major review, however, found that interventions like yoga, meditation, tai chi, acupuncture, mindfulness, religious/spiritual practices, cognitive behavior therapy and coping did tend to normalize cortisol levels, and were associated with reductions in inflammatory processes.
A “health education program” and three CBT studies also reportedly increased cortisol levels in their mix of “ME/CFS” patients. Another review of various interventions in fibromyalgia, however, to improve cortisol, found only “small overall effects”. A 2-month isometric yoga program in ME/CFS did improve fatigue and reduce anxiety levels but did not affect cortisol levels.
One CBT study, interestingly, found that reduced sleep duration was associated with low cortisol levels. Poor sleep has been associated with reduced morning cortisol levels before. Researchers have recognized that poor sleep could be responsible for some of the low morning cortisol levels in ME/CFS. On the other hand, cortisol does affect the sleep-wake cycle.
Past, more rigorously done studies, suggested that the average dose used (@12 mg/day) in a big North Dakota-based study was right on, but the improvement ratings (77-78% reported improvement) seemed optimistic.
This was not a rigorously done study. It was not placebo-controlled or blinded; neither the doctors in the study, the disease criteria, the method of measuring symptoms, etc. were reported. It reported that over 60% of the participants (in every disease with over 20 participants) significantly improved – a remarkably high number. The main source of information on adrenal suppression came from a 1957 paper. No tests were done to determine if adrenal suppression had occurred.
No rationale was given for providing the broad spectrum antibiotic to everyone who failed initially to significantly improve. That addition seemed strange given worries about antibiotic resistance and possible gut issues.
The only ME/CFS hydrocortisone study to last several months did find adrenal suppression in some patients – but importantly, at a much higher dose than used in this study, or that is used by ME/CFS/FM experts. While the limited evidence we do have (1 one-month study) suggests that the low-dose hydrocortisone use is safe, we don’t have any data on the effects of low-dose hydrocortisone for more than a month. The ME/CFS experts who use it do appear confident, however, that it’s safe.
The authors suggested that a 5-day hydrocortisone regimen be used to control flares – an interesting idea. They also proposed that people who have trouble identifying flares (are in a flare all the time?) stay on the drug during the weekdays and off on weekends.
While this study wasn’t anything close to being a rigorously controlled study, it did use a dose that some evidence suggests – and some ME/CFS experts believe – is safe. The very high rate of positive outcomes seems unrealistic, but ME/CFS studies do suggest that a subset of ME/CFS patients may readily respond to low dose hydrocortisone supplementation.
Tinkering with hormones is inherently a bit risky. Without large, rigorously controlled studies to demonstrate its efficacy and safety, the use of low-dose hydrocortisone will likely remain controversial.
This content was originally published here.