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Neuroendocrine Aspects of CFS
By Dimitris A. Papanicolaou, M.D.
A panel of experts convened in March
2001 for the second in a series
of scientific symposia on chronic fatigue syndrome (CFS).
The symposium, which focused on abnormalities
in the neuroendocrine
system, was sponsored by The Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS) Association of America
and the U.S. Centers for Disease Control.
Several studies have suggested a neuroendocrine
component to CFS,
but the exact role abnormalities play is still unknown. The meeting was organized as a "scientific court,"
a format used by the National Institutes of Health to accelerate current research.
Following a day of presentations by
experts, an independent panel
composed of well-respected researchers and practitioners in the fields of biostatistics, endocrinology,
epidemiology, immunology, internal medicine, neurology, psychiatry, and sleep disorders, as well as two
CFS advocates, developed a consensus statement on the key issues surrounding the role of the neuroendocrine
system in CFS.
Key findings of the panel are summarized
The nature of hypothalamic-pituitary-adrenal
(HPA) axis function
in CFS needs to be clarified.
evidence of HPA axis dysfunction in CFS, but testing has yielded inconsistent results. This may be due
in part to the relapsing-remitting nature of the illness and to differences in research study designs.
The panel suggested that studies comparing CFS patients with and without HPA axis dysfunction be conducted.
Cytokine abnormalities, neuroendocrine
intolerance, and CFS may be interconnected. Cytokines
are chemical messengers that stimulate the HPA axis when the body is under stress or experiencing an infection.
A number of cytokines, including tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6), have
been implicated in CFS. The panel noted these findings are intriguing in view of research connecting CFS
and a family of blood pressure-related disorders called orthostatic intolerance (OI). There is evidence
that excessive secretion of inflammatory cytokines such as TNF-alpha may induce OI, although more studies
delineating the links between these abnormalities are needed.
CFS is not synonymous with depression. The panel agreed that CFS should be differentiated from major depression. Individuals
depression have an activated HPA axis, but HPA axis studies in CFS patients have been contradictory. Studies
have shown that corticotrophin-releasing hormone levels in the cerebrospinal fluid are normal or even
low in CFS patients, while they are often increased in depressed individuals. And as a group, persons
with CFS also demonstrate a diminished cortisol response compared to persons with depression.
The panel suggested that these data
may point toward a potential
biological marker for persons with CFS compared to persons with depression.
No link has been established between
CFS and stress. Past research has suggested that stressors such as viral
life events, physical abuse, and automobile accidents may cause CFS symptoms. However, the panel agreed
that there is not enough evidence to date to establish a link between specific stressors and neuroendocrine
abnormalities in CFS and related disorders.
Sleep abnormalities may contribute
to CFS symptoms. Sleep disturbances can cause increased production of IL-6
and some researchers believe that they contribute significantly to excessive daytime sleepiness in CFS.
However, the panel pointed out that studies of the association between HPA axis alteration, cytokine secretion
patterns, and sleep abnormalities in CFS patients are needed.
More research is needed to define
the neuroendocrine aspects
of CFS. The panel outlined future research
studies to evaluate stressors previously hypothesized to cause CFS; test treatment strategies, such as
drugs to affect HPA axis activity; and identify neuroendocrine activity in larger populations of persons
with CFS, including those that fit specific subgroups of the disease.
Panelists also suggested ways to overcome
potential research barriers,
such as conducting long-term studies to capture the fluctuations in symptom severity most CFS patients
experience and developing human experimental models to identify potential biological markers for the illness.
The CFS assessment symposia series
is designed to examine the role
of the neurological, endocrine, circulatory, and immune systems in CFS. The symposia gather experts to
evaluate research findings, identify the most promising next steps, define research and funding priorities,
and create research collaboration teams.
To preserve the ability to publish
the statement in the medical literature,
the complete document is not yet available for distribution.
Dr. Papanicolaou is Assistant Professor of Medicine,
Department of Medicine/Endocrinology, and chair of the neuroendocrine symposium consensus panel.