Phoenix Rising: The Cortisol Edition (Sept 2008) by Cort Johnson

News



Exciting News From The Whittemore-Peterson-Institute Check out this video from Channel 2 News in Reno. In it Dr. Judy Mikovits stated that a blood test measuring immune agents to diagnose chronic fatigue syndrome (ME/CFS) could be ready within a year. The WPI is also in the process of identifying a new virus that is present and may cause or contribute to the disease. Heady stuff!

Click on Major Medical Breakthroughs at the bottom of the page to access the interview.

Dr. Natelson Talks! - Dr. Natelson is his energetic self in this hour-long radio interview.

Treating Orthostatic Intolerance - Phoenix Rising now has a four part section on treating orthostatic intolerance. Comments and suggestions are always gratefully accepted.

EBV/CMV Patients - Check out Carlito's excellent blog as he plows through what his test results mean and examines different treatment options.

When Pushing Stops Working" We all  know 'pushing' just makes things worse in this disease. Check out this three part Teleconference recording from the Northern Virginia CFIDS group on other alternatives on managing this illness. 

The Federal Advisory Committee on Chronic Fatigue Syndrome (CFSAC) News - Amongst the hundred or so NIH advisory committees only a very few are focused on one disease and chronic fatigue syndrome (ME/CFS) is one of them; the CFSAC's charter was renewed for two more years - good news for the ME/CFS community.

Focus on Artists with Chronic Fatigue Syndrome (ME/CFS) 

  • Bobby Lounge  tore up the 2006 New Orleans Jazz Festival and then disappeared. It turns out he's had ME/CFS since 1985.  Check out his website and the piece NPR did on him.
  • Tamara Lewis is a singer-songwriter with a gorgeous voice. Check out her YouTube video and her website.
  • Christina Gombar - this literary provocateur is in the midst of publishing a memoir of her life in the financial sector with ME/CFS.  A former financial writer and insurance company employee she's looking for lawyers and financial experts as resources. Check out her beautiful website
Success Snapshots! - Success Snapshots is a new section in the Phoenix Rising Newsletter. They're short reports distilled from e-mail messages I occasionally receive on treatment successes. Dr. Nancy Klimas recently said that chronic fatigue syndrome (ME/CFS) patients do get well (or at least significantly better) more often than we think - just not enough to celebrate. See them below.

RESEARCH SECTION: Cortisol, Cortisol, Cortisol! - The Cortisol Edition

Background: Dozen’s of studies over the past twenty years have made the cortisol easily the most intensively studied substance in chronic fatigue syndrome (ME/CFS). Why study cortisol? Cortisol is the endpoint of the stress response centered in the HPA axis (hypothalamus-pituitary-adrenal) and low cortisol can many of the symptoms found in chronic fatigue syndrome (ME/CFS) such as fatigue, malaise, sleepiness and muscle and joint pain. To top it off, cortisol has a major effect on how well our immune system functions.

Dig Deeper: Check out "The Hypocortisolism in Chronic Fatigue Syndrome (ME/CFS) - Artifact or Central Factor?" 

The results of the Pharmacogenomic’s studies prompted the Centers for Disease Control (CDC) to focus
strongly on cortisol and follow up gene studies suggest ME/CFS patients may have an inherent
susceptibility to the negative effects of low cortisol.

Success Snapshots

Sick for 10 years Lynn was ill enough at one point that her internist, fearing she had congestive heart failure, felt she should see a cardiologist. At the end of her rope with regards treatment she reluctantly tried the exercises in Donna Eden's book 'Energy Medicince'. They helped but she was still severely impaired. Then she tried Ashok Gupta's Amygdala Retraining program and within 6 weeks reported she went from @40% to 85% functioning; her riding car is history, her cane is gone and she's working out on a stationary bicycle. Essentially she said "I no longer have CFS. Now I'm just a fat middle-aged lady who's way out of shape. But not for long." To read her story click here.

The triad of low cortisol readings in ME/CFS, fibromyalgia and post-traumatic stress syndrome have
lead some to posit that low cortisol play an important role in multi-systemic disorders associated
with fatigue and pain. Other researchers see low cortisol levels in rheumatoid arthritis and other
autoimmune disorders that chiefly strike women and wonder about a cortisol/immune connection.

Still studies that show cortisol levels are only mildly low in chronic fatigue syndrome (ME/CFS) (and
sometimes not even that) may lead one to legitimately question how important a role this substance
could play in this disease. The studies reviewed below suggest that even after all this study that
cortisol still remains a dynamic field of inquiry. Dr. Holtorf not only believes cortisol levels can
play a major role in the disease but that those ‘mildly low’ cortisol levels may not be mildly low
after all. The CDC study at the end of the newsletter suggests that low cortisol levels probably play
a more important role in women than men. Another recent study suggests low cortisol levels may impact
ME/CFS patients ability to respond to other treatments – that study, however, will appear in another
newsletter.

Paper of the Month: Cortisol to the Rescue?
A Case for the Use of Low-Dose Cortisol in Chronic Fatigue Syndrome (ME/CFS

Holtorf, K. 2008. Diagnosis and treatment of hypothalamic-pituitary-adrenal axis dysfunction in patients with chronic fatigue syndrome and fibromyalgia. Journal of Chronic Fatigue Syndrome 14;3

A former of patient of Dr. Holtorf who returned to health created the Fibro-Fatigue Centers, a string
of clinics across the U.S. that treat chronic fatigue syndrome (ME/CFS), FM and other diseases using
Dr. Holtorf’s protocol. Dr. Holtorf and Dr. Teitelbaum – who is now the director of the FF Centers –
are both known for advocating the use of low dose hormones in combination with a comprehensive
treatment plan to correct often undetected hormonal abnormalities – a controversial approach.

Something in their approach seems to be working. In the latest edition of Fatigued to Fantastic Dr.
Teitelbaum cites unusually high recovery rates: 40-50% of patients back to 85-100% functioning,
another 20-30% with significant improvement. In this paper Dr. Holtorf cites an ongoing study
indicating that 94% of his patients had significant improvement by their 4th visit with average energy
levels more than doubling (3.0-6.7 to 7.6 at 9th visit). They weren’t well (6.7 out of 10 on the
energy scale) but they clearly improved a great deal.

Dr. Holtorf uses a multi-dimensional program in which hormones play just one (if a major) role. Could
the use of low dose hormones - something of a minority approach in chronic fatigue syndrome (ME/CFS)
treatment – be making the difference? In this paper Dr. Holtorf lays out the case for low dose hormone
treatment in this disease and addresses concerns that low dose hormone treatment could, over time,
lead to hormonal suppression.

Evidence - Dr. Holtorf believes that studies thus far do, in spite of contrary interpretation, support a finding of significant dysfunction of the hypothalamus-pituitary-axis (HPA) in chronic fatigue syndrome
ME/CFS. The HPA axis is one of two major stress response systems in the body. The main stress hormone
produced by the HPA axis is cortisol. Dr. Holtorf argues that studies of basal cortisol levels (while
the system is at rest) miss the central problem; an inability of this major stress response system
to respond properly to stress.

Another (rather disillusioning) problem concerns the tests themselves; Dr. Holtorf provides some
evidence indicating that the immunoassays typically used by labs to test for cortisol levels (e.g.
Bayer Advia Centaur, Abbot TDx, DPC Immulite 2000, Amerlex, Baxter Diagnostics) are inaccurate and
often overestimate cortisol levels compared to more accurate testing protocols (gas
chromatography/mass spectrometry (GC/MS) and high performance liquid chromatography (HPLC)).

Success Snapshot

After seven years of ill health but no diagnosis or improvement X visited a chiropractor to help her with her painful neck, shoulders and headaches. He advised her to visit an endocrinologist specializing in ME/CFS etc. who informed her that she did indeed have ME/CFS; her thyroid was out of synch, she had low vitamin D and high homocysteine levels and adrenal exhaustion. He put her on diatroxin + eltroxin, vitamin D, high levels of B-12, B6, DHEA, N-acetyl choline (liver), Co Enzyme Q10 and testosterone (!).                                                               Within a week she reported she was feeling much better – her breathlessness was reduced and the pain and weakness in her arms and legs had almost all disappeared. She called her improvement ‘miraculous’ but then caught a very bad cold and had to revert to complete bed rest but at last report was doing much better.


A more important problem lies in the types of tests used. Dr. Holtorf believes the problem in
producing cortisol in CFS does not lie in the adrenal gland (which directly produces cortisol) but
higher up in the pituitary or hypothalamus (where the initiating signals come from). While baseline
cortisol and ACTH stimulation tests have had inconsistent results, tests that examine central HPA axis
activity (using CRH, IL-6, d-fenfluramine, IST, metyraponine) have consistently (15/16) demonstrated
abnormalities.

Hormonal Suppression – The fear when taking cortisol (cortisone) is that doing so will permanently
turn off the adrenal gland. The consequences of hormonal suppression are significant and include
adrenal damage, bone loss and immune suppression. Dr. Holtorf believes, however, that hormonal
suppression is a function of the higher doses in pharmaceutical drugs and does not occur with the
lower levels in the bio-identical hormones (<15 mg) he uses. Far from depressing HPA axis and immune
functioning, he reports that low dose hormone supplementation actually improves HPA axis and immune
functioning, including specifically NK cell activity – a key immune player in ME/CFS.

Treatment - Dr. Holftorf noted that a low dose cortisol treatment trial (5-10 mg/day) for one month resulted in significant reductions in fatigue and disability in ME/CFS. Dr. Teitelbaum’s comprehensive treatment trial administered cortisol if one of the four following conditions were met: baseline cortisol levels
<12; ACTH stimulation tests resulted in <7 cortisol increase in 30 minutes or <11 increase at 60
minutes; 60 minute cortisol levels <28; or if symptoms suggested cortisol suppression was present.
This comprehensive treatment plan resulted in significant improvements with no evidence of adrenal
gland suppression.

Dr. Holtorf reported that a very large ongoing study (4000 patients) at the Fibro Fatigue Centers
indicates that physicians using a simpler formula had significant positive results; 85% of patients

Notice: Prescribing low doses of bio-identical hormones for patients with low-normal cortisol levels is
controversial. While several prominent physicians regularly prescribe bio-identical hormones others
are emphatically against prescribing hormones unless clear evidence of hormone insufficiency is
present. One prominent physician told me that taking hormones would make me feel better at first but that my adrenal gland would turn off leaving me dependent on hormone supplementation.

were ‘improved’ by the 4th visit; 56% reported ‘significant improvement’ and 40% ‘substantial
improvement’ by the 4th visit and 62% reported significant improvement and 46% substantial improvement
by the 7th. Side effects were rare and minimal when they occurred.

Dr. Holtorf proposes that low dose cortisol (<15 mg/day) offers the possibility of substantial
benefits for CFS with much less risk than many of the standard therapies (NSAIDS, anti-depressants,
muscle relaxants, low-dose narcotics) now used to treat the disease.
    Takeaway Points  
  • Dr. Holtorf presents evidence suggesting that cortisol levels in many chronic fatigue syndrome (ME/CFS) patients are lower that most tests indicate.
  • Dr. Holtorf reports that preliminary results from an large ongoing study at the Fibro-Fatigue Centers suggests that many patients at the Centers do significantly improve over time. This study has not been published.
  • Dr. Holtorf asserts that the use of low dose bio-identical hormones is more effective and less risky than many treatments commonly used in the disease.

 Stress Response – What Stress Response?

Jerjes, W., Taylor, N., Wood, P. and A. Cleare. 2006. Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome. Psychoneuroendocrinology 32: 192-198.

Most studies have found that the HPA axis (hypothalamus-pituitary-adrenal) is functioning at a lower
than normal level in ME/CFS. Oddly enough, the HPA axis is designed to turn itself off. Every time
cortisol – the endpoint of the HPA axis - is released, it inhibits further HPA axis activity. The body
does this because the stress response – which cortisol triggers - is too potent a reaction to have it
turned on all the time.

One theory suggests that this ‘negative feedback response’ has gone too negative in chronic fatigue
syndrome (ME/CFS). It posits that CFS patients turn off their stress response too quickly; every time
the HPA axis ramps up, it shuts itself down before it can effectively respond to the challenge at
hand. This could make it difficult for patients to raise the energy needed to engage in all
sorts of ‘stressful’ activities.

These UK researchers gave the participants a drug (prednisolone) designed to test how fast their HPA
axes shut down. A greater fall in chronic fatigue sydndrome (ME/CFS) patient’s cortisol levels would suggest that they were
turning off their stress response more quickly than normal.

The Findings These researchers found that ME/CFS patients did shut down their ‘stress response’ more quickly than normal; the prednisolone suppressed cortisol output by about 20% more in ME/CFS patients (p<.0001) than in the healthy controls. This also suggests upregulated GR/MR (glucocorticoid/ mineralocorticoid) receptor activity was present in the disease.

These UK researchers noted that enhanced negative suppression of cortisol is also found in several
diseases sometimes associated with chronic fatigue syndrome (ME/CFS) such as post-traumatic stress
syndrome, burnout syndrome and chronic pelvic pain.

Early Life Stress and Chronic Fatigue Syndrome (ME/CFS)


Van Den Eede F, Moorkens G, Hulstijn W, Van Houdenhove B, Cosyns P, Sabbe BG, Claes SJ. 2007. Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome. Psychol Med. 2007 Sep ;1-11

As in the previous study, these Belgian researchers also stressed the HPA axis to see how it
responded, but they dug a bit deeper. They used a different HPA axis stressor (dexamethazone) and
examined whether early life stress influenced how well the HPA axis was functioning. They looked at
early life stress because some theories suggest that high rates of early life stress (ELS) may

Success Snapshot

One man who was about to go on disability did a sleep study which uncovered some abnormalities that caused his doctor put him on an unusual regimen; Wellbutrin in small doses early in the morning and late at night; he reported that much to his amazement he was on the way to complete recovery - his problem it turned out was simply very poor sleep.

predispose people to ME/CFS.

Study Findings: Interestingly, the rates of ELS in the ME/CFS and control group did not differ
significantly.

They found that, yes, ME/CFS patients as a whole did appear to be turning off their HPA axis more
quickly than normal. When they teased out the ME/CFS patients with ELS from those without ELS they
found, contrary to expectations, that only the patients without ELS had abnormal HPA axis functioning
(!); the HPA axis of the patients with ELS appeared to be working just fine. This suggests, of
course, that ME/CFS patients with early life stress are a different subset of patients than those
without early life stress.

Early Life Stress, the CDC and Chronic Fatigue Syndrome (ME/CFS) – One CDC study suggested that people who experience ELS are more prone to develop chronic fatigue syndrome (ME/CFS) than those who do not. This Belgian study, ironically enough, suggests that ME/CFS patients with early life stress have a normal stress response and it’s the ME/CFS patients without early life stress that have the abnormal stress response. Given this study’s findings one could make a case that ME/CFS patients with ELS have been obscuring the magnitude of the stress response related problems in those ME/CFS patients without ELS.

This study follows a string of nervous system studies by Dr. Natelson that suggest ME/CFS patients
with mood disorders differ from patients without those difficulties. What’s really intriguing and on
the surface paradoxical about these studies is that they’ve found more abnormalities in ME/CFS
patients without these mood problems/psychological trauma than in those with them.

Take Away Points

ME/CFS patients do appear to shut down their stress response more quickly than normal. This could account for the low cortisol levels sometimes found and contribute to their post-exertional fatigue and immune problems.

ME/CFS patients did not have statistically higher rates of early life stress than the healthy controls.

Patients with early life stress had normal HPA axis readings while patients without early life stress had abnormal ones. This and other studies suggest that patients with mood disorder/psychological trauma may have a different type of ME/CFS than those without those problems.

Cortisol and Women: A Special Role for the Hormone?

Nater, U., Maloney, E., Boneva, W., Gurbaxani, B, Lin, J-M., Jones, J., Reeves, W. and C. Heim. 2007. Attenuated morning salivary cortisol concentrations in a population-based study of persons with chronic fatigue syndrome and well controls. J. Clin Endo. Metab. Pub. ahead of print.


The CDC continues full speed ahead with their focus on the HPA axis side of the stress response. This
was yet another study on cortisol.

Study - The CDC studies are a bit different; they’re usually very rigorous in their exclusionary factors,
they employ patients derived from random sampling efforts not from clinics

Success Snapshot

Testing found that one woman had low levels of progesterone - a steroid hormone that is a precursor to cortisol and which plays a role in the menstrual cycle, pregnancy, etc. Her endocrinologist had no suggestions but her gynecologist did; she put her on progesterone and six months she was still reporting significantly improved energy.

(they believe this is
important); they’re using the ‘Empirical Definition’ not the standard 1994 International (Fukuda)
definition to gather their patients; and they’re measuring fatigue, symptoms and disability according
to standardized measures.

(Oddly enough they don’t refer to the ‘Empirical Definition’. They simply state they used the
‘standardized reproducible criteria’ recommended by the International Study Group (ISG) which was
based on the 1994 definition. This suggests that the new definition simply quantifies the 1994
definition which steps over the fact that the new definition greatly discounts fatigue and appears to
focus more on emotional issues. It also ignores the fact that the final definition was developed by a
small in-house group of CDC researchers and that some of the members of the ISG were appalled by the
new definition; it is not simply a quantification of the International Definition)

Findings – This study found low morning cortisol levels in women but not in men with ME/CFS compared
to healthy controls. The finding that only females had low morning cortisol levels was new and
interesting since it could help explain why more women have this disease than men. When they examined
symptom, fatigue and disability scores they found that the low morning cortisol was correlated with
physical fatigue.

Reduced Adrenal Capacity? For the first time that I can remember the CDC suggested that the low
cortisol levels might reflect reduced adrenal capacity presumably because studies suggest that early
morning cortisol in part reflects adrenal capacity. Most of the speculation regarding cortisol thus
far has focused on damage higher up – at the hypothalamus or pituitary or in the brain's signals to
them but here the CDC is suggesting that the problem may lie at the last rung of the axis – the
adrenals. This mirrors Baschetti’s controversial proposal that ME/CFS is an Addison’s-like disease and
these researchers noted that ME/CFS shares many symptoms with Addison’s disease.

Dr. Reeves, citing the less than spectacular results of a short-term trial of hydrocortisone (the standard treatment for Addison's disease) does not recommend cortisol supplementation in ME/CFS.  (This leaves us with the odd situation of Dr. Reeves not recommending adrenal hormone supplementation (hydrocortisone)for what he suggests may be an adrenal deficiency  and Dr. Holtorf recommending adrenal hormones ( bio-identical hormones) for a problem he believes originates in the hypothalamus.)

Cortisol – An Overstudied Hormone?   Because chronic stress can affect cortisol (and HPA axis
functioning) it’s possible that the lowered cortisol levels in ME/CFS simply reflect the very
stressful nature of their lives and have nothing to do with triggering the disease. (We should know
more about this soon; Dr. Taylor is measuring cortisol levels as mononucleosis patient’s lapse into
ME/CFS. She should be able to tell us when the low cortisol levels appear in patients with an
infectious trigger.)

While this study confirmed again that the HPA axis part of the stress response is underactive in
ME/CFS, it also cast doubt on how important low cortisol is. The paper started off noting that low
cortisol is associated with fatigue, sleepiness, malaise and muscle and joint pain, but, of the
fifteen different scales measured, the low cortisol levels were only significantly correlated with
physical fatigue – not an impressive result for such a supposedly important agent.

The ability to measure symptoms and disability is a big benefit of the empirical definition.
Ironically, this time it suggested a major emphasis of the CDC’s program may not be so major at all.
(But hold on – a recently released study suggests cortisol may play a bigger role than this study
suggests).

Takeway Points

Low morning salivary cortisol levels in women with ME/CFS but not men suggest cortisol may play a special role in women

The CDC suggests ME/CFS may be an Addison’s-like disease that reflects low adrenal capacity.

A analysis of symptoms suggests cortisol contributes to the physical fatigue in the disorder but not other symptoms

Conclusions: Aside from the agreement that low cortisol levels do play a role in some ME/CFS patients illness there seems to be little consensus on how big a role they play or how to fix them. One side, lead by Drs. Holtorf and Teitelbaum believes bio-identical hormone supplementation is often an essential component of a patients treatment regime and have some evidence that it works. Another side which includes the CDC but also some other prominent physicians are strongly against even low dose hormonal  supplementation unless there is clear evidence of a significant hormonal deficiency. ME/CFS patients and their physicians will have to decide how to proceed.