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Diagnosis and Treatment
of Hypothalamic-Pituitary-Adrenal (HPA)
Axis Dysfunction in Patients
with Chronic Fatigue Syndrome (CFS)
and Fibromyalgia (FM)
Kent Holtorf, MD
ABSTRACT. There is controversy regarding the incidence and signifi-
cance of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in
chronic fatigue syndrome (CFS) and fibromyalgia (FM). Studies that
utilize central acting stimulation tests, including corticotropin-releasing
hormone (CRH), insulin stress testing (IST), d-fenfluramine, ipsapirone,
interleukin-6 (IL-6) and metyrapone testing, have demonstrated that
HPA axis dysfunction of central origin is present in a majority of these
patients. However, ACTH stimulation tests and baseline cortisol testing
lack the sensitivity to detect this central dysfunction and have resulted in
controversy and confusion regarding the incidence of HPA axis dys-
function in these conditions and the appropriateness of treatment. While
both CFS and FM patients are shown to have central HPA dysfunction,
the dysfunction in CFS is at the pituitary-hypothalamic level while the
dysfunction in FM is more related to dysfunction at the hypothalamic
and supra-hypothalamic levels. Because treatment with low physiologic
doses of cortisol (<15 mg) has been shown to be safe and effective and
routine dynamic ACTH testing does not have adequate diagnostic sensi-
Kent Holtorf is Medical Director, Holtorf Medical Group, Inc., Torrance, CA, and
Chief, Medical Advisory Board, Fibromyalgia and Fatigue Centers, Inc., Dallas, TX.
Address correspondence to: Kent Holtorf, MD, Holtorf Medical Group, Inc., 23456
Hawthorne Boulevard, Suite 160, Torrance, CA 90505 (E-mail: kholtorf@cox.net).
Published papers were identified and reviewed via a computerized literature search
of the PubMed database with associated keywords.
Journal of Chronic Fatigue Syndrome, Vol. 14(3) 2007
Available online at http://jcfs.haworthpress.com
©2007 by The Haworth Press. All rights reserved.
doi:10.1300/J092v14n03_06 59
tivity, it is reasonable to give a therapeutic trial of physiologic doses of
cortisol to the majority of patients with CFS and FM, especially to those
who have symptoms that are consistent with adrenal dysfunction, have
low blood pressure or have baseline cortisol levels in the low or low-nor-
mal range. doi:10.1300/J092v14n03_06 [Article copies available for a fee
from The Haworth Document Delivery Service: 1-800-HAWORTH. E-mail ad-
dress: <docdelivery@haworthpress.com> Website: <http://www.HaworthPress.
com> © 2007 by The Haworth Press. All rights reserved.]
KEYWORDS. HPA axis dysfunction, hypothalamic-pituitary-adrenal
axis, chronic fatigue syndrome, fibromyalgia, CFIDS, cortisol, hydro-
cortisone
INTRODUCTION
Chronic Fatigue Syndrome (CFS) and fibromyalgia (FM) are dis-
abling conditions that are shown to be present in 0.5-5% of the popula-
tion and often coexist (1-3). Treating CFS and FM patients is often
frustrating for physicians as there is no clear etiology or treatment, and
the use of standard recommended treatments that don’t address the
underlying pathophysiology, including NSAIDs, antidepressants and
muscle relaxants, are largely ineffective and have significant side-ef-
fects (4-7). Reliance on these medications results in a poor prognosis
and is unsatisfying for both patients and physicians (8-18). There is un-
likely a single causative agent or process occurring in these conditions.
The hypothalamic-pituitary dysfunction that is present in the majority
of CFS and FM patients results in HPA axis dysfunction that is often not
detected by standard testing done in a clinical setting, as these tests are
designed to detect primary adrenal insufficiency and have poor sensitiv-
ity for secondary or tertiary adrenal insufficiency (19-58). In addition,
this hypothalamic-pituitary dysfunction results in secondary and/or ter-
tiary hypothyroidism (as well as evidence of thyroid resistance) that is
not detected with standard thyroid testing (27,59-69), and low growth
hormone production that is also not detected by standard testing
(27,60,70-74). There has also been shown to be associated mitochon-
drial dysfunction (75-78), sleep disorder (79-84), immune dysfunction
(85-95), chronic infections (96-105), autonomic dysfunction (106-108),
gastrointestinal dysfunction (109-113) and coagulation dysfunction
(114-119) in these patients.
60 JOURNAL OF CHRONIC FATIGUE SYNDROME
A multi-faceted treatment approach that addresses the above abnor-
malities, including treatment with hormonal supplementation despite
seemingly normal levels and treatment of the mitochondrial dysfunc-
tion, sleep disorder, chronic infections, immune dysfunction, gastroin-
testinal dysfunction and the coagulation dysfunction is now the
standard of care by experts who specialize in the treatment of CFS and
FM (65,69,78,120-146). There are seemingly contradictory studies re-
garding the incidence of HPA axis dysfunction in these conditions.
However, a clearer understanding of pathophysiology of these condi-
tions demonstrates that the negative results are largely due to a lack of
sensitivity of the testing utilized and the improper use of standard cut-
offs to denote normal function and not because there is an absence of
HPA axis dysfunction.
EVIDENCE FOR SIGNIFICANT HPA AXIS DYSFUNCTION
There are a large number of studies that assess basal cortisol levels in
CFS and FM patients as a primary focus or as part of a subsequent stim-
ulation test. These are of limited value as they fail to assess the function
of the HPA axis during stress and lack sensitivity in detecting central
HPA axis dysfunction. The majority of studies measuring 24-hour urine
cortisol levels in CFS and FM patients have demonstrated significantly
lower values in the CFS/FM patients (22,29,30,32,33,45-49). As with
baseline measures of serum cortisol, twenty-four hour urine cortisol
lacks sensitivity at detecting central HPA axis dysfunction because it
does not necessarily assess the HPA axis dysfunction during stress. Ad-
ditionally, the wide individual variation of 24-hour cortisol excretion in
normal individuals due to varying stress levels over the 24 hours signifi-
cantly decreases sensitivity. Ten studies were identified that assess
24-hour urine cortisol levels in CFS and FM patients with six demon-
strating a significant decrease in 24-hour urine cortisol in CFS/FM pa-
tients and one demonstrating reduced levels that did not reach statistical
significance (22,29,30,32,33,45-49). The majority of studies that mea-
sured 24-hour urine involve very small numbers of patients and con-
trols, limiting the sensitivity, while the largest study to date by Cleare et
al. involving 121 CFS patients and 64 controls demonstrated signifi-
cantly decreased 24-hour urine cortisol levels in CFS patients that
averaged approximately 30% lower than healthy controls (47).
The lack of sensitivity of the 24-hour urinary cortisol levels is dem-
onstrated by the fact that two of the four negative studies also performed
Original Research 61
stimulation tests (IST or IL-6) and both demonstrated HPA axis dys-
function despite having normal or non-significantly reduced 24-hour
urine cortisol levels (32,33).
One of the two remaining negative studies was a small study by Maes
et al. in which 24-hour cortisol levels were measured in patients with
FM, major depression and post traumatic stress disorder (PTSD) com-
pared to normals (49). This study consisted of 14 FM patients and 17
normals. The contradictory findings of this study may be explained by
the fact that it appears that they excluded patients who were on any med-
ications and it also appears that these patients were not previously diag-
nosed with FM prior to the study. This would tend to include only those
with very mild disease and exclude those with moderate or severe
symptoms, who would more likely have been previously diagnosed
with FM and require medications for symptomatic relief.
The second of the two remaining negative studies was by Young et
al. that compared 24-hour urinary cortisol between 22 CFS patients and
24 controls (48). The difference in these results may be explained by
different patient characteristics than the other studies, including the fact
that these patients had the shortest mean duration of symptoms of all the
24-hour urine cortisol studies, being only 2.5 years, compared to the
other studies that had mean durations of 3.6 to 9.7 years.
There are a large number of seemingly contradictory studies that
measure basal cortisol levels or utilize standard dynamic ACTH stimu-
lation tests to evaluate HPA axis function in CFS and FM, which has led
to confusion and controversy as to the incidence of HPA axis dysfunc-
tion in these conditions. One likely contributing cause of the confusion
and controversy is that it has been shown that the plasma cortisol
immunoassays used by the majority of laboratories, institutions and
studies suffer from considerable inaccuracy and variance and can sig-
nificantly overestimate serum cortisol levels when compared to gold
standard assays such as gas-chromatograph/mass spectrometry (GC/
MS) and high performance liquid chromatography (HPLC). This has
led to controversy, a high degree of misdiagnosis and the misclassi-
fication of patients as having normal HPA function despite significant
dysfunction or severely underestimating the severity of the dysfunction
(147-151).
For instance, Cohen et al. compared three commonly used cortisol
immunoassays (Bayer Advia Centaur, Abbott TDx and DPC Immulite
2000) and HPLC to determine serum cortisol levels and found a huge
variation in results with concordance in only 44% of patients. The
immunoassays were shown to overestimate the serum cortisol levels by
62 JOURNAL OF CHRONIC FATIGUE SYNDROME
an average of 70% (35%, 79%, and 95%, respectively, for each assay)
without appropriate adjustment of the reference ranges by the assay
manufacturers. This resulted in the misclassification of 44-56% of pa-
tients depending on the assay used. The Centaur assay produced results
that were over 480% of that of the HPLC standard, the TDx assay pro-
duced results that were up to 590% of the standard and the Immulite as-
say produced results that were 770% of the standard (147).
De Brabandere et al. evaluated the performance of three cortisol
immunoassays commonly used by laboratories in the U.S. and Europe
(Diagnostic Products Corp (DPC), Amerlex and Baxter Diagnostics)
(149). They measured cortisol levels in 15 patient samples and 10 com-
mercially prepared control serum standards in duplicate and compared
the results with those obtained via the gold-standard GC/MS. The mea-
sured cortisol results on the commercially prepared control samples
showed that the assays averaged only 11% higher than when measured
via the GC/MS. However, the results on the patient samples demonstrated
a severe inaccuracy of these assays commonly used in commercial labo-
ratories. The mean deviation of the reported cortisol concentrations that
were below 13 ng/ml (370 nmol/l) was +21%, +91%, and +83% for
each assays, respectively. These differences were not reflected in the re-
spective kit reference ranges. For instance, the upper reference range for
the Amerlex assay is only 12% higher than the upper reference range of
the DPC assay despite averaging over 40% higher on the same speci-
mens. Baxter quotes an upper reference range that is significantly lower
than the Baxter assay (552 nmol/l vs. 690 nmol/l) despite having the
strongest positive overall bias. The lower limit for the Amerlex assay is
only 9% greater than the DPC assay (152 nmol/l vs. 158 nmol/l) despite
averaging over 60% higher on the same specimens. These studies dem-
onstrate that a seemingly normal baseline or stimulated cortisol level re-
ported by a laboratory cannot be relied upon to accurately rule out
significant hypocortisolism.
Further confounding results is the fact that CFS and FM patients are a
very heterogeneous group in terms of illness severity and duration and
associated psychiatric comorbidities, which likely influence HPA dys-
function. In addition, there is the significant normal variation in cortisol
levels in normal individuals. A more important fact is, however, that a
multitude of studies have demonstrated the HPA axis dysfunction in
these conditions is central (hypothalamic or pituitary), not a primary ad-
renal insufficiency. Consequently, it is of no surprise that these studies
appear to have inconsistent results because baseline cortisol levels and
ACTH dynamic testing have very low sensitivities in detecting central
Original Research 63
HPA axis dysfunction and fail to diagnose the majority of patients with
known significant central HPA axis dysfunction (29,31,35-44). Be-
cause a normal result with such testing does not rule out significant dys-
function, it is not a recommended means of detecting this abnormality.
Low dose (1 μg ACTH) stimulation may be slightly more sensitive than
conventional (250 μg ACTH) testing, but it still suffers from very poor
sensitivity and misses approximately 50% of individuals with estab-
lished central hypoadrenalism determined by IST, d-fenfluramine,
ipsapirone, CRH stimulation or metyrapone testing (35-41,44,152).
Studies that use appropriate testing for individuals with secondary or
tertiary hypoadrenalism, including IST, metyrapone testing and stimu-
lation testing using CRH, IL-6 and d-fenfluramine, have consistently
demonstrated significant HPA axis dysfunction in CFS and FM pa-
tients. Of the 16 studies identified that used such testing, all but one of
these studies demonstrated HPA axis dysfunction with abnormal
ACTH and/or cortisol secretion (19-33,41).
CHRONIC FATIGUE SYNDROME
Demitrack et al. studied the functional integrity of the various com-
ponents of the HPA axis in 30 patients with CFS and 72 normals with an
average duration of illness of 7.2 ±1.0 years. They performed CRH (bo-
vine 1 μg/kg) stimulation testing and graded ACTH stimulation testing.
They also compared the levels of evening serum free and total cortisol,
cortisol binding globulin (CBG) and corticotropin releasing hormone
(CRH) in the cerebrospinal fluid and measured 24-hour urinary cortisol
levels (19).
They found significantly lower evening cortisol levels in CFS pa-
tients vs. controls (3.2 μg/ml ±0.3 vs. 5.3 ±0.73) and 24-hour urinary
free cortisol excretions that were 40% lower in the CFS patients (122.7
nmol/l vs. 203 nmol/l). Interestingly, the level of cortisol binding globu-
lin CBG was also significantly higher in the CFS patients making the
free cortisol index almost 70% lower in these patients (2.9 vs. 8.9). This
elevated CBG is significant because it results in an overestimation of
bioavailable and free cortisol levels, and if confirmed, it may be further
contributing to the lack of sensitivity of both basal and dynamic testing
by overestimating cortisol levels in these patients because most of the
studies have utilized total cortisol levels when comparing CFS and FM
patients to normals. This potential of overestimation of serum cortisol
64 JOURNAL OF CHRONIC FATIGUE SYNDROME
levels would be additive to the overestimation of actual cortisol levels
by commonly used immunoassays discussed earlier (147,149).
This study found a significant attenuated net integrated ACTH re-
sponse to CRH (128 ±26.4 vs. 225 ±34.5) (p < 0.04) demonstrating
central HPA axis dysfunction. With ACTH stimulation testing, there
was an initial increased sensitivity to ACTH with a subsequent reduced
maximal response. Although this cortisol response to ACTH was clearly
abnormal for all of the patients with CFS in this study, the dose response
curve varied. There was an initial exaggerated response followed by an
abnormally blunted response, which is not the case for patients with
simple primary or secondary adrenocortical insufficiency and demon-
strates hypothalamic involvement in the HPA axis dysfunction in these
patients (19).
Scott et al. (1998) performed CRH (bovine 100 μg) stimulation tests
on 14 CFS patients with an average illness duration of 4.8 ±0.6 years
(range 1.5-10 years) as compared to 14 controls. There were lower basal
ACTH and cortisol levels in the CFS patients, but it did not reach statis-
tical significance. The delta-ACTH response in the CFS group (21.4 ±
4.3 ng/l) was significantly lower than that in the controls (51.9 ±8.5) (p
< 0.005). The delta-cortisol levels were also similarly attenuated in the
CFS group (197.7 ±21.6 nmol/l) vs. the healthy controls (310.5 ±21.6
nmol/l), demonstrating central HPA axis dysfunction in these patients
(20).
Scott et al. (1999) again evaluated the HPA axis in CFS patients by
performing CRH (bovine 100 μg) stimulation tests on 13 CFS patients
as compared to 13 controls. Patients had a mean duration of illness of
5.0 years. This study found that 8 out of 13 CFS patients had lower stim-
ulated ACTH levels than the lowest ACTH response in the normal con-
trols, being 21.0 ±4.5 ng/l in the CFS patients as compared to 57.8 ±11
ng/l (p = .005) in normal controls. The delta-cortisol response in 9 of the
12 CFS patients was lower than the lowest delta-cortisol in the control
group (157.6 ±40.7 nmol/l in the CFS group compared to 303.5 ±20.9
nmol/l in the control group [p = 0.01]), again demonstrating central
HPA axis dysfunction in CFS patients (21).
Cleare et al. (2001) performed CRH (human 1 μg/kg), IST and d-fen-
fluramine stimulation testing in 37 medication free CFS patients.
Patients had a mean duration of illness of only three years. Thirty-two
patients were treated with low dose (either 5 mg or 10 mg cortisol per
day). With human CRH stimulation testing, there were similar ACTH
responses between groups with AUC cortisol values being reduced in
Original Research 65
CFS patients as compared to controls (206 ±213 nmol/l-h vs. 313 ±257
nmol/l-h [p = 0.069]). When ACTH was controlled for, the CFS patients
had a significantly reduced release of cortisol (p = 0.016). The differ-
ence in the abnormality seen in this study as compared to Demitrack et
al., Scott et al. (1998) and Scott et al. (1999) could be due to different
patient characteristics. The average duration of illness in this study was
only three years, while the average duration of illness in the Demitrack
et al. and the Scott et al. studies were 7.2, 5 and 4.8 years, respectively.
In addition, human CRH was used at 1 μg/kg as compared to bovine
CRH, which is more potent and has a longer half life, being used in the
Demetrik and Scott et al. studies. Scott et al. used human CRH at a
higher average dose of 100 μg, as well. Interestingly, the patients who
responded to treatment with clinical improvement had a normalization
of the previously blunted cortisol response to CRH, while those who did
not clinically respond had no significant change in the endocrine
parameters before and after treatment, demonstrating a lack of adrenal
suppression and a potential improvement in HPA axis function with
physiologic doses of cortisol (22).
With d-fenfluramine stimulation testing, there was again a trend for
lower cortisol response (p = 0.077) without a significant difference in
ACTH levels. When ACTH responses were controlled for, cortisol re-
sponses were significantly reduced (p = 0.033). There was no signifi-
cant difference in ACTH or cortisol responses between groups with IST
assessment, but there was significantly reduced urine 24-hour cortisol
levels in CFS patients vs. controls (p = 0.025) (22).
Inder et al. compared 24-hour urinary cortisol levels and performed
CRH (bovine 1 μg/kg) stimulation testing on 12 CFS patients and 11
controls. They found no significant difference in 24 hour urinary cortisol
levels, basal ACTH, basal cortisol levels, stimulated ACTH or stimu-
lated cortisol levels. The illness duration was not stated. This difference
may be explained by the heterogeneity of this population and the small
study size. The study size would require a 40% difference between
groups to distinguish a difference (23).
Gaab et al. performed IST on 18 CFS patients with an average illness
duration of 5.6 years (range 1.4-14 years) and 17 controls. They found a
significantly blunted ACTH response to IST that was 40% less in the
CFS group compared to controls, demonstrating central HPA axis dys-
function in these patients. Interestingly, they also performed two proce-
dures mimicking real-life stressors and also found significantly lower
66 JOURNAL OF CHRONIC FATIGUE SYNDROME
ACTH responses in the CFS patients as compared to controls, demon-
strating central HPA axis dysfunction (24).
Bearn et al. performed IST and d-fenfluramine stimulation testing on
nine CFS patients and ten normal controls. The average duration of ill-
ness was 5.7 years with a range of 1-15 years. All but one had signifi-
cant myalgia and were not on medication for 12 weeks prior to study.
There was a delayed and attenuated ACTH and cortisol response to IST
that was consistent with hypothalamic-pituitary dysfunction but due to
the small sample size, it did not reach statistical significance (25).
There was a significantly increased ACTH response with d-fenflura-
mine stimulation with a decreased cortisol response that also did not
reach statistical significance due to the sample size. This is consistent
with hypothalamic dominant dysfunction with a centrally inhibited ad-
renal response to ACTH. A hypothalamic dysfunction with a primary
adrenal dysfunction is also possible, but unlikely, considering normal
adrenal response to ACTH under different study conditions. These pa-
tients’ ACTH and cortisol response was more indicative of FM patients
(discussed below) and demonstrates a more hypothalamic/supra-hypo-
thalamic dominant dysfunction that is seen in the FM patients as com-
pared to the hypothalamic/pituitary dysfunction typically seen in CFS
patients. The authors did not state if any of the patients also met the cri-
teria for FM, but all but one had significant myalgia, so it is likely that
they did have FM, thus explaining the results (25).
Dinan et al. (1997) demonstrated a blunted release of ACTH in re-
sponse to ipsapirone, a serotonin agonist, in 14 CFS patients vs. 14 con-
trols (4.4 ±0.6 ng/l vs 14.6 ±1.6 ng/l), demonstrating central HPA axis
dysfunction in these patients (26).
FIBROMYALGIA
Riedel et al. (1998) injected CRH (bovine 100 μg) along with a simul-
taneous injection of TRH, GHRH and LHRH in 16 FM patients and 17
controls. They found elevated basal levels of ACTH and cortisol and an
exaggerated ACTH response with no difference in stimulated cortisol
levels, demonstrating a hyporesponsive adrenal response to ACTH.
This is most consistent with a hypothalamic or a supra-hypothalamic
dominant dysfunction rather than a primary adrenal insufficiency. They
also found significantly elevated prolactin levels on stimulation with
significantly reduced TSH secretion, free T3 production and growth
Original Research 67
hormone secretion, all demonstrating hypothalamic-pituitary dysfunc-
tion (27).
Griep et al. (1993) performed CRH (human 100 μg) stimulation test-
ing and IST on 10 FM patients and 10 controls. They also found a statis-
tically significant enhanced ACTH response and a relative adrenal
hypo-responsiveness in the FM patients as compared to controls with
both the IST and CRH testing, indicating a tertiary (hypothalamic or su-
pra-hypothalamic level) hypoadrenalism (28).
Griep et al. (1998) compared the HPA axis function in 40 FM pa-
tients with an average illness duration of 10.7 ±7.2 years, 28 patients
with chronic low back pain and 14 controls. They used a combination of
tests that included CRH (human 100 μg) stimulation testing, very low
dose (0.025 μg/kg) and low dose (0.1 μg/kg) ACTH stimulation tests
and 24-hour urinary cortisol evaluations. This study also showed a sig-
nificantly abnormal HPA axis in FM patients after CRH stimulation
with an ACTH hyper-responsiveness and a relative adrenal hypo-re-
sponsiveness, indicating a tertiary (hypothalamic or supra-hypotha-
lamic level) hypoadrenalism (29).
There was also significantly decreased 24-hour urine cortisol levels
in the FM patients compared to the controls, but there was no difference
in the evoked cortisol levels with either the very low dose or the low
dose ACTH simulation tests between the three groups, indicating that
there is not a primary adrenal dysfunction. This study also further dem-
onstrates and supports other studies that show that ACTH stimulation
testing is an insensitive means of detecting central HPA axis dysfunc-
tion and is, therefore, not a recommended method of evaluation in these
patients (29,31,36-39,152).
Crofford et al. performed CRH (bovine 1 μg/kg) testing and 24-hour
urinary free cortisol levels in 12 FM patients and 12 controls. The FM
patients had an average duration of illness of 6.2 ±3.1 years. This study
found a non-statistically significant exaggerated ACTH response to
CRH with a statistically significant decrease in net cortisol response
(p < 0.02), demonstrating a hypothalamic dominant dysfunction of the
HPA axis of FM patients. They also found a statistically significant de-
crease in 24-hour urinary free cortisol levels (p < 0.002) (30).
Calis et al. performed metyrapone testing and 1 μg ACTH stimula-
tion tests on 22 FM patients and 15 matched controls. After metyrapone
administration, 95% of FM patients had lower 11-deoxy-cortisol than
the lowest level in the healthy controls, while only 45% of FM patients
had low cortisol responses to the ACTH simulation test (31). This dem-
68 JOURNAL OF CHRONIC FATIGUE SYNDROME
onstrates central HPA axis dysfunction in these patients, but ACTH
stimulation testing will miss approximately half the individuals with
significant dysfunction and is not a recommended means of evaluating
the HPA axis in these patients (29,31,36-39,152).
Kirnap et al. performed IST as well as 1 μg and standard ACTH stim-
ulation testing on 16 FM patients and 16 controls. They found signifi-
cant reduced basal cortisol levels in the FM group (p < 0.0001) as well
as significantly reduced responses to all three stimulation tests (p <
0.0001), demonstrating significant central HPA axis dysfunction in
these patients (ACTH levels were not measured). They also found that
if the standard cutoffs were used with the ACTH simulation test, most
of the patients would have been misdiagnosed as normal (40).
Adler et al. performed stepped hypoglycemic hyperinsulinemic clamp
studies, performed ACTH infusions and evaluated 24-hour urinary free
cortisol levels in 15 FM patients and 13 controls. The average duration
of illness was 9 ±8 years. Baseline 24-hour urinary free cortisol levels
were not significantly different between the two groups, but basal
ACTH levels were significantly lower in FM patients (2.8 ±1.7 pmol/l)
as compared to the control group (5.0 ±2.9 pmol/l). The ACTH levels
in response to hypoglycemia were significantly reduced in the FM
group, with an average integrated response being 68% of that of the
control group. Baseline hypoglycemic stimulated and ACTH stimu-
lated cortisol levels were not significantly different. These results of a
diminished ACTH response are in contrast to the above studies demon-
strating an exaggerated ACTH response in FM patients and more simi-
lar to the results involving CFS patients. There is significant overlap in
those diagnosed with FM and CFS and this may have been a factor in
this study. Additionally, this group had a much longer duration of ill-
ness than the FM patients in the previously discussed studies and differ-
ent methodologies could also explain the differences (33).
Torpy et al. performed 24-hour urine cortisol levels and administered
IL-6 stimulation tests to 13 FM patients and 8 controls. There was a
trend to lower 24-hour urine cortisol levels in FM patients vs. controls
(40.7 ±5 ng/24-hours vs. 57.0 ±9.9 ng/24-hours) although it did not
reach statistical significance. They found no significant difference in
peak cortisol or ACTH levels between the two groups, but the FM group
was shown to have a significant delay in the ACTH response, with peak
levels not occurring until 96 ±6 minutes vs. 68.6 ±10.3 minutes in the
control group. This delayed ACTH response with a trend to lowered
24-hour urine cortisol levels supports a dysfunction at or above the hy-
Original Research 69
pothalamic level. This delayed ACTH response as compared to the ex-
aggerated ACTH response to CRH in FM probably reflects differences
in the principle site of action of these agents and supports HPA axis
dysfunction at or above the hypothalamic level (32).
TREATMENT
In a randomized crossover trial, Cleare et al. 1999 treated 32 CFS pa-
tients with a mean duration of illness of 3 years (range 2.3-3.75 years)
with low dose cortisol (5-10 mg/day) and placebo for one month in a
randomly assigned order. This study found significant improvements in
fatigue and disability in those treated with low dose cortisol but not with
placebo (p = 0.009). Twenty-eight percent of the patients improved to
normal levels with treatment, and follow-up IST demonstrated that
there was no suppression of endogenous adrenal function with treat-
ment. In fact, those who responded to treatment had an improvement in
HPA axis function via CRH stimulation testing, demonstrating the ef-
fectiveness and appropriateness of this treatment (22,146).
Blockmans et al. performed a 6-month randomized, placebo-con-
trolled, double-blind, crossover study of 80 patients with CFS using a
combination of 5 mg cortisol and 50 μg of fludrocortisone. Patients had
an average duration of illness of only 2.5 years (1.3-5). There was sig-
nificant improvement in fatigue scores with treatment as measured with
an Abbreviated Fatigue Questionnaire (p = 0.004), but there was a sig-
nificant placebo response so it was not significantly different from pla-
cebo. There was no difference in fatigue scores as measured by a visual
analog scale. There was significant improvement in the Mental Factor
of the Short Form Health Survey compared to placebo and also in the
Physical Factor but not compared to placebo. Depression scores im-
proved with treatment vs. placebo. ACTH simulation tests were per-
formed at 0, 3, and 6 months. The baseline ACTH stimulation tests were
normal and none of the patients had any evidence of adrenal suppres-
sion with treatment (153).
The less impressive response in this study as compared to the Cleare
study is potentially explained by different patient characteristics. These
patients had a much shorter duration of illness and were recruited from
different patient populations. The Cleare study recruited patients from
clinics that specialize in CFS in England and Blockmans et al. recruited
patients from a tertiary care university hospital in Belgium, and they ap-
peared to have excluded those with ulcers, hypertension, glaucoma or
70 JOURNAL OF CHRONIC FATIGUE SYNDROME
diabetes but did not exclude those with fatigue related illnesses. These
patients appeared likely to be an especially heterogeneous group with a
multitude of disease processes.
Mckenzie et al. performed a randomized, placebo-controlled, dou-
ble-blind 12-week therapeutic trial with 25-35 mg of cortisol to 30 CFS
patients and 35 controls. Patients met the more rigorous 1988 criteria
for CFS and were assessed with a daily wellness scale for 12 weeks. The
study found that 66.7% of patients improved with treatment, with most
patients reporting a modest but significant difference vs. placebo as
measured by at least a 5, 10 or 15 point improvement. A five or more
point improvement was seen in 53% of the cortisol treated patients vs.
29% receiving placebo (p = .04), a 10 point improvement was seen in
33% of the cortisol treated patients vs. 14% of controls (p = .07) and a
15 point improvement was seen in 20% of cortisol treated patients vs.
6% of controls (p = .08) (154).
Three patients in the treatment group withdrew due to ineffectiveness
and four withdrew from the placebo treatment (three due to ineffective-
ness and one due to a rash). Five of the cortisol treated patients did not
have pretreatment wellness scores so they could not be evaluated. There
was no significant correlation between response and the pretreatment
basal or ACTH stimulated cortisol levels. Five patients in the treatment
group had a depressed cortisol response in the post treatment ACTH
simulation testing. However, the doses used in this study are considered
by many researchers and clinicians that specialize in CFS/FM to be in-
appropriately high for treatment of this condition (54,120,124,125,136,
155-162) and significantly higher than the studies that demonstrate a
lack of adrenal suppression with lower doses of 5-15 mg/day (22,120,
146,153,156,162).
Teitelbaum et al. performed a randomized, double-blind, placebo
controlled, intent to treat study on 72 FM (69 also met CFS criteria) pa-
tients (38 active and 34 placebo) that documents the effectiveness of an
integrative treatment approach to CFS and FM that includes low dose
cortisol (7.5-20 mg/day) (120). The patients underwent an integrative
multi-system treatment protocol based on an algorithm that took into
account laboratory tests as well as signs and symptoms. Potential treat-
ments included antidepressants, levothyroxin, cortisol, fludrocortisone,
DHEA, testosterone and antimicrobial treatments. Cortisol was admin-
istered if there was a baseline cortisol level = 12; the ACTH stimulated
cortisol increase was < 7 at 30 minutes, < 11 at 60 minutes or the 60
minute cortisol was < 28; the HgbA1C was < 5.1; or if patients had three
significant symptoms consistent with adrenal dysfunction. Cortisol was
Original Research 71
given to 29 of the 38 patients at some time during the 3 month study.
Overall, 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 overall response
(p < 0.0001). No patients were found to have any adrenal suppression
with post-treatment ACTH simulation tests. While this study does not
separate out cortisol’s overall effect, it provides the basis for demon-
strating that an integrative multi-system treatment approach that in-
cludes low dose cortisol is highly safe, effective and appropriate in the
treatment of these conditions. This integrative approach is now consid-
ered by many who specialize in the treatment of CFS/FM to be the cur-
rent basic standard of care (65,69,120-146) and has served as a building
block for more advanced therapies and algorithms. Interestingly, a
sub-analysis demonstrated that antidepressants had no significant bene-
ficial effect on the patients’ outcome scores (p < .0001) (120).
Currently, our center has tracked over 500 consecutive patients that
met the CDC criteria for CFS and/or the American College of Rheum-
atology criteria for FM (240 met criteria for CFS, 14 met the criteria for
FM and 259 met criteria for both). The computerized tracking system
consists of the tracking of the patients’ average overall energy level and
sense of well-being (SOWB) on each visit as well as the frequency and
severity of 10 symptoms that includes fatigue, muscle pain, stiffness,
cognitive function, headaches, insomnia, unrestful sleep, gastrointesti-
nal dysfunction and sore throat. Before each visit, patients rated their
energy and sense of well being on a scale of 1-10 (1 being low and 10
being high) and their individual symptom frequency and severity on a
scale of 1-10 (10 being constant and 1 being rare for frequency and 10
being severe and 1 being mild for severity). Patients had seen on aver-
age 7.2 different physicians for treatment of their CFS and/or FM with-
out significant improvement prior to being seen at our center. Patients
were treated based on a multi-system integrative treatment algorithm
that incorporates therapies based on the most recent understanding of
the pathophysiology of these conditions (due to its complexity, a de-
scription of the algorithm is beyond the scope of this review). The treat-
ment algorithm did include low dose cortisol after the second visit if
symptoms were consistent with adrenal dysfunction based on 24 symp-
toms and/or having low blood pressure and/or having a baseline cortisol
level in the low or low-normal range. If patients met the protocol crite-
ria, they were given a therapeutic trial of 5-15 mg of timed-released
cortisol per day. Patients were also given fludrocortisone if they had
signs of neurally mediated hypotension.
72 JOURNAL OF CHRONIC FATIGUE SYNDROME
Analysis revealed (prepublication ongoing data collection) that 94%
of patients had overall improvement by the 4th visit with 75% noting
significant overall improvement and 62% reporting substantial overall
improvement. The majority of patients continued to improve in subse-
quent visits. The average energy levels and average SOWB increased
significantly. The average energy level more than doubled by the 4th
visit, going from an average of 2.98 at baseline to 6.39 at the 4th visit
and then to 6.77 and 7.67 at the 7th and 9th visits, respectively. The av-
erage SOWB also more than doubled by the fourth visit, increasing
from a baseline average of 3.03 then increasing to 6.29, 7.45, and 6.83
on the 4th, 7th, and 9th visit, respectively. There were no significant
side-effects from low dose cortisol in these closely monitored patients
(136).
Subsequently, over 40 physicians were trained to utilize a more sim-
plified treatment algorithm in 17 centers across the country. In this
multi-center study, over 4000 consecutive patients diagnosed with CFS
and/or FM were treated with this simplified algorithm and tracked via
the same computerized patient assessment system. This prepublication
ongoing data collection demonstrated that 85% of patients improved by
the 4th visit, with 56% and 40% reporting significant and substantial
improvement, respectively, by the 4th visit. This increased to 62% and
46% by the 7th visit (137).
While these two studies are not placebo controlled and do not allow
the evaluation of cortisol as a sole treatment of CFS/FM, as cortisol was
only a part of the multi-system treatment protocol that included numer-
ous therapeutic interventions, cortisol supplementation was shown to be
a beneficial and safe therapeutic intervention with little or no risk as part
of a multi-system integrative treatment protocol. It is extremely un-
likely that such dramatic improvements were due to a placebo effect be-
cause these patients had been typically seen by numerous physicians
without improvement and such patients have been shown to have little
placebo responses (163).
SIDE EFFECTS AND SAFETY
Because physiologic doses of cortisol (<15 mg) do not increase lev-
els beyond normal levels, it is exceedingly safe and is not associated
with adverse effects associated with pharmacological doses of corti-
costeroids, including adrenal suppression, bone loss and immune sup-
pression (22,54,120,136,137,146,153,155-157,162,164-176). A review
Original Research 73
by Jefferies of 1000 patient-years of treatment with physiological doses
of cortisol found that the only undesirable side effect was acid indiges-
tion and skin rashes due to allergies to the tablets’ fillers in a few
patients (155).
As opposed to pharmacological doses of corticosteroids, physiologi-
cal doses (< 15 mg) of cortisol have been shown not to cause adrenal
suppression (22,120,146,153,156,162) and have been shown to actually
improve HPA axis function (22). This is counterintuitive to what physi-
cians are taught and have found with higher pharmacological doses of
glucocorticoids. Also, physiologic doses of cortisol have been shown to
improve cellular and hormonal immunity, including natural killer cell
activity (155,157,164-171,177), which has been found to be a consis-
tent abnormality in CFS patients (85-88). This is also counter-intuitive
to physicians because of the well-known immune suppression that is
seen with pharmacological doses of corticosteroids.
The longest randomized placebo controlled studies (over 2 years)
that assessed bone loss with the use of low dose corticosteroids
(= equivalent to 40 mg of cortisol) have demonstrated that there is no
significant increase in bone loss vs. placebo with such treatment
(172-176). The fact that these studies, while considered low dose, were
considerably higher than the recommend doses for CFS and FM pa-
tients, demonstrates that using cortisol supplementation at doses less
than 15 mg would not have any adverse effects on bone loss.
Low physiologic doses of cortisol (<15 mg) carry little risk and have
a risk/benefit ratio that compares favorably to treatments that are con-
sidered standard therapies for CFS and FM, including antidepressants,
NSAIDS, muscle relaxants and low-dose narcotics. For instance, there
is considerable anecdotal evidence supporting the use of SSRI’s in CFS
and FM, and most physicians feel they are significantly beneficial in
these patients. However, randomized blinded placebo controlled trials
have consistently shown little benefit, with the majority of patients not-
ing significant side effects with up to a third of patients having to dis-
continue treatment due to side effects (4,5). The newer dual acting
antidepressants such as duloxetine have been shown to be beneficial in
FM but suffer from poor tolerability (6,7). A randomized controlled
trial demonstrated that duloxetine was of benefit in women with FM but
not in men. In addition, 90% of patients had significant side-effects in
the treatment group and 44% had to discontinue treatment due to
moderate or severe side-effects (6,7).
In contrast, side effects are very rare and significant side effects are
essentially non-existent with physiologic doses of cortisol. An even
74 JOURNAL OF CHRONIC FATIGUE SYNDROME
more compelling argument can be made when the considerable risks,
that include death, of other common treatments for CFS and FM, in-
cluding NSAIDS, muscle relaxants and low dose narcotics, are com-
pared to the negligible risk of physiologic doses of cortisol.
SUMMARY
There is ample evidence that there is HPA axis dysfunction of central
origin in CFS and FM but the exact level or levels of dysfunction are
less clear. The data are consistent with mixed hypothalamic-pituitary
dysfunction in CFS and FM with CFS having more pituitary dominant
dysfunction while FM patients have more hypothalamic or supra-hypo-
thalamic dominant dysfunction. This is consistent with the fact that the
hypothalamus has significant pain modulating properties and hypotha-
lamic dysfunction has been shown to increase pain sensation (178).
The HPA axis is an incredibly complex group of specialized neuronal
tissue, with the hypothalamus being the most complex part of the CNS.
The hypothalamus consists of somewhat arbitrarily defined regions and
nuclei that include the pariventricular, arcuate, suprachiasmatic, ante-
rior, ventromedial, dorsomedial, posterior and supraoptic nuclei with
extensive interaction with different afferent and efferent pathways from
the thalamus, basal ganglia, cerebral cortex, reticular formation and
visceral centers of the brainstem. The reticular formation and visceral
centers of the brainstem connect with the hypothalamus through the
mammillary peduncle and the dorsal longitudinal fasciculus. There is
also significant input via locus ceruleus, vagal nuclei, periaqueductal
gray and nuclei of the solitary tract and from the piriform cortex and
amygdala, olfactory nuclei and the hippocampus. While the studies
clearly support HPA dysfunction at the pituitary and hypothalamic
levels, it is not surprising that the precise level and mechanism is
unclear.
Potential mechanisms occurring in CFS include pituitary dysfunc-
tion with hyporesponsive pituitary corticotrophs, enhanced negative
feedback and/or deficient hypothalamic secretion of CRH. FM patients
have more dysfunction at the hypothalamic level or have abnormal hy-
pothalamic input along with hyporesponsive adrenals to ACTH. There
is convincing evidence of central regulation of adrenal sensitivity to
ACTH (179). Interestingly, depressed patients are characterized by
hyperactivity of all components of the HPA axis, including increased
sensitivity to ACTH by the adrenals and increased CRH mRNA expres-
Original Research 75
sion, with resultant hyercortisolism. Given the complexity of neuronal
interaction in this system, it is unlikely that the precise nature of HPA
axis dysfunction in CFS/FM patients will be elucidated in the near fu-
ture. This certainly does not mean these patients should not be treated
until such understanding is complete.
CONCLUSION
There is a complex interaction of HPA axis dysfunction in these pa-
tients, and it is becoming clear that the majority of patients with CFS
and FM suffer from clinically significant adrenocortical dysfunction.
Current methods of testing are very poor at assessing the area of dys-
function in these complex interactions, but despite this, all studies uti-
lizing IST, CRH and/or metyrapone testing have shown abnormal
results in these patients. Studies that utilize 24-hour urinary cortisol lev-
els have consistently shown HPA axis dysfunction with only a few stud-
ies showing normal levels in CFS and FM patients. On the whole,
ACTH stimulation testing has shown to be abnormal in about 50% of
CFS/FM patients. This would be the expected percentage if 100% of the
patients had HPA axis dysfunction of central origin, as this test suffers
from very poor sensitivity for central HPA axis dysfunction and would
be expected to miss approximately 50% of these patients. In addition,
the inaccuracy of the most commonly used cortisol assay further con-
founds results. The ACTH stimulation test has clearly been shown to
lack sufficient sensitivity to differentiate CFS and FM patients with
HPA axis dysfunction from those with normal function. A normal result
cannot be used with any confidence in these patients to rule-out signifi-
cant dysfunction; thus, it cannot be recommended as a useful test to
guide treatment in these patients. The more central acting stimulation
tests are also not recommended for routine clinical use because interpre-
tation is problematic, they are burdensome and expensive and carry
significantly more risk than the most appropriate treatment, a therapeu-
tic trial of physiological doses of cortisol.
Physiologic replacement of cortisol at doses of 5-15 mg/day have
been shown to be safe, with little or no associated risk, and have the po-
tential for significant clinical benefit. Cortisol treatment carries signifi-
cantly less risk and a greater potential for benefit than treatments
considered to be the standard of care in the treatment of CFS/FM, in-
cluding antidepressants, muscle relaxants and narcotics. The current
evidence supports the use of physiologic doses of cortisol as an appro-
76 JOURNAL OF CHRONIC FATIGUE SYNDROME
priate component of a multi-system treatment protocol for CFS and FM,
and a therapeutic trial of cortisol should be considered 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.
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