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 “General theory of inflammation: patient self-administration of hydrocortisone safely achieves superior control of hydrocortisone-responding disorders by matching dosage with symptom intensity” brought cortisol and hydrocortisone (Cortef – 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 authors reported that the participants ingested an average of 12 mg hydrocortisone per day – which is less, the authors asserted, than the 15 mg/day which produces adverse effects in the most sensitive adults. The 15 mg/day dose rate was based on the 1957 study.
The authors did not state, though, whether the 12 mgs/day occurred during the flare period or if it was an average of the doses taken during the induction and flare periods.
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|
The doses provided in the 3-week induction phase were extremely high – up to five times higher, in fact, than the doses (25-35 mg/day) which produced adrenal suppression in a several month long ME/CFS study. (See below). These appear to be types of doses typically used to treat inflammation.
Adrenal suppression occurs when the adrenal glands fail to produce normal amounts of cortisol often after a patient has been on higher levels of steroids. It is a serious matter and needs to be dealt with carefully.
Since the authors did not determine if adrenal suppression had occurred we don’t know if 37 mg/day (<68 kg), or 48 mg.day (68-114kg), or 77 mg/day (!) (>114 kg) induced adrenal suppression over a shorter period of time (three weeks). While the authors reported that no symptoms suggestive of overdosing or adrenal suppression occurred the British Medical Journal Best Practices states that it can occur within 3 weeks.
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|
- Cortisol affects metabolism, inflammation, blood pressure, blood sugar, energy production and even the sleep-wake cycle.
- Studies generally find low cortisol levels are present in ME/CFS/FM
- A huge study involving about 80 doctors and 600 people with fibromyalgia and 25 with ME/CFS (and over a 1000 others with other diseases) found that about 75% benefitted from low dose hydrocortisone (Cortef) supplementation (<15 mgs/day).
- The study included an induction period in which everyone took hydrocortisone for a month and then a flare reduction period in which the participants took it for five days following the beginning of a flare. Some people took it throughout the month while taking a hydrocortisone holiday on weekends.
- The amount of hydrocortisone given during the three-week induction period was extremely high – up to five times higher than a dose which produced adrenal suppression in some ME/CFS patients – but over several months.
- The authors asserted that the low dose of the drug plus the holidays prevented adrenal suppression where the adrenal glands stops producing cortisol from occurring. While the authors stated that the average dose during the flare period was 12 mgs/day, if some of the participants took the drug five days a week 4 times a month they could be taking almost 20 grams a day – and be in danger of adrenal suppression.
- Tests for adrenal suppression were not done but the authors reported so signs of it occurred.
- From the simplistic monitoring system to the lack of blinding or cortisol testing etc. the study was rudimentary indeed.
- Past placebo controlled hydrocortisone studies in ME/CFS, while small, do suggest that a subset of patients may significantly benefit from supplementation. Baseline cortisol testing, does not, however, reveal who might benefit. Why some benefit and others do not is unclear.
- Several ME/CFS experts do embrace hydrocortisone supplementation in low levels (5-15 mgs. depending on the doctors.) They assert that adrenal suppression does not occur at these levels.
- Some studies have been able to use mind/body and behavioral techniques to normalize cortisol levels. Other studies have not.
- The large, long term studies needed to fully assess the efficacy and safety of low dose hydrocortisone supplementation have not occurred in these diseases.
The authors apparently feel that any flare must be hit hard as the recommended doses are quite high – and could easily lead to adrenal suppression if taken for very long. If someone from 68-114kg. took the flare reducing dose five days a week for the entire month (as they recommend for some people) they would average 16 mg/day. Someone >114 kg would average 20 mg/day and possibly be flirting with adrenal suppression. It appears that most people, though, limited their hydrocortisone usage to lower amounts.
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.
Two Different Approaches
Tinkering with the hormones carries real risks. The North Dakota study and the ME/CFS experts used two distinctly different approaches to hydrocortisone.. The North Dakota approach used doses more designed to snuff our inflammation than to provide adrenal support. They used a three week high dose induction period to stabilize the patients and then quickly hit flares hard with higher-dose, quickie 5-day hydrocortisone regimen. They also proposed that some patients can safely stay on the higher dose regimen over long periods of time time so long as they did not take hydrocortisone on weekends.
The doses given during the three week induction period were high enough to suggest that adrenal suppression was a real possibility. The authors reported, though, that no adverse side effects suggestive of overdose occurred.
The North Dakota study was not rigorously done. It was not placebo-controlled or blinded; neither the doctors in the study, the disease criteria, the method of measuring symptoms, etc. were provided. The average 12 mg/day dose per patient was not explained. The study also reported that the participants in a wide variety of diseases improved by over 60% – a remarkably high number. The main source of information on adrenal suppression came from a 1957 paper. Despite the high doses given during the induction period, no tests were done to determine if adrenal suppression had occurred.
No rationale was also 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.
Instead of using hydrocortisone to respond to flares, the ME/CFS practitioners that prescribe low dose hydrocortisone (5-15 mgs/day) have their patients use it consistently – and at much lower doses.
The only ME/CFS hydrocortisone study to last several months did find adrenal suppression in some patients, but at much higher doses (25-35 mgs/day) than typically used by ME/CFS/FM experts 5-15 mgs/day).
While the limited evidence we do have (1 one-month study) suggests that the hydrocortisone used in this manner is safe, no data exists on the safety of long term low-dose hydrocortisone use in ME/CFS/FM. The ME/CFS/FM experts who use it do appear confident, however, that when used in low doses it is safe. .
ME/CFS studies suggest that some ME/CFS patients do readily respond to everyday doses (5-15 mgs) that were significantly lower than the doses used in the North Dakota study. The higher dose, hit the inflammation hard approach used by the doctors in the North Dakota study is a very different approach indeed.