New research has revealed sublte hormonal deficiencies in the neuroendocrine systems of people with chronic fatigue syndrome (CFS). These finding may explain many symptoms of the disorder and could lead to new treatment strategies. The study was conducted by a collaborative team of researchers from NIAID, the National Institute of Mental Health and the National Institute of Child Health and Human Development.

The hallmark of CFS is debilitating fatigue of unknown causes lasting at least 6 months. Other common symptoms include feaverishness, tender lymph glands, muscle and joint aches, sleep disturbances, depression and difficulty concentrating.

The number of people with CFS in the United States is unknown, but estimates range in the tens of thousands.  Although most people diagnosed with CFS are young adult women, the conditon occurs in people of all ages and races and of both sexes.

The research team found that, on average, levels of the hormone cortisol were lower in the blood and urine of the 30 CFS patients studied than in 72 healthy volunteers. Cortisol is secreted by the adrenal gland in reponse to stress. It has long been known that even a suble deficiency of cortisol can be associated with lethargy and fatigue.

Normally, when the body responds to a stressor - whether to a virus or bacterium, an environmental toxin, or a pshychological event - a complex series of events occurs in the endocrine (hormone) system.  The hypothalamus, a small area at the base of the brain, first secretes a brain chemical called corticotropin releasing hormone(CRH), which activates the pituitary gland to secrete adrenocorticotropin hormone (ACTH).

ACTH, in turn, stimulates the adrenal gland to produce cortisol. This hormonal circut was examined in the 18 women and 12 men with CFS in the study, all of whom met the criteria for CFS established by the Centers for Disease control. None of the patients was allowed to use drugs, alcohol, tobacco or caffeine for 2 weeks before the study began in order not to compromise the results. All underwent a series of clinical tests involving administration of small doses of CRH and ACTH.
The levels of several hormones were subsequently analyzed in blood, urine, and cerebrospinal fluid samples taken from the patients.

Based on their findings, the investigators concluded that the cortisol deficiency seen in patients with CFS resulted from a CRH deficiency.

In addition to controlling ACTH and cortisol secretion, CRH helps to increase energy lvels through its direct effect on the brain.  Thus, two hormonal abnormalities - a CRH deficiency and the resultant cortisol deficiency - could each contribute to the overall symptoms and course of CFS, according to the researchers.

The endocrine deficiency found in the study patients also offers a possible explanation for the depressive symptoms that may accommpany CFS.  Although the hormone profile of the CFS patients studied is the opposite of what is seen in "classic"melancholic depression, low CRH levels have been seen in patients with other depressive syndromes.

These syndromes include some traditionally characterized as psychological disorders, such as specific subtypes of major depression, as well as depressive syndromes associated with Cushing's disease and hypothyroidism. Finding a common central nervous system defect in these illnesses underscores the fact that these depressive syndromes are all fundamentally physical illnesses caused by a biochemical imbalance, according to the researchers.  The investigators suggest that insufficient stimulation of certain parts of the brain by cortisol or CRH could account for the lethargy and increased need for sleep seen in CFS.  Further studies are in progress to determine which contributes most significantly to the fatigue in patients with CFS - the CRH deficiency or the cortisol deficiency alone, or the two deficiencies together.

Importantly, among individual CFS patients, the investigators found no associatioon between their hormone levels and a past or present history of psychiatric illness.

Stephen E. Straus, M.D., chief of MAID's Laboratory of Clinical Investigation and a collaborator on the study, has investigated various aspects of CFS for the past 12 years.  He was originally intrigued by the possibilty that a chronic infection could cause the disorder and might explain the high levels of viral antibodies found in many people with CFS.

"There continues to be hints of viruses being associated with CFS," Dr Straus said, "but I am excited by the alternative new hypotheses raised about the syndrome by the current findings. Because cortisol is a potent suppessor of immune responses, a mild reduction in cortisol levels could allow the immune system to remain overactive, leading to findings such as a higher-than normal antibody levels".

Although the research findings have not proved that low CRH and cortisol levels cause CFS, the researchers said their results suggest that hormonal balance might be restored by treating patients with small amounts of cortisol.

They caution, however, that cortisol levels cannot be easily measured. In additon, simply treating patients with cortisol could be dangerous. Administering cortisol to a CFS patient could signal to the hypothalamus that the supply of cortisol is adequate and that the secretion of CRH is unnecessary. Thus, the CRH deficiency could be exacerbated.

Despite these concerns, Dr. Straus said, "careful study could reveal a means to use the present findings to help alleviate the associated fatigue, lethargy, muscular aches and feverishness of CFS".

Reference:
mark Demitrack, Janet Dale, Stephen Straus, Louisa Laue, Sam Liswak, Markus Kruesi, George Chrousos, and Philip Gold.
"Evidence for Impaired Activation of the Hypothalamic-Pituitary-Adrenal Axis in Patients with Chronic Fatigue Syndrome" Jornal of Clincial Endrocrinology and Metabolism 73, 1224-34(1991).

University of Michigan Medical Center (M. Demitrack) National Institute of Allergy and Infectious Diseases (J. Dale, S. Straus) National Institute of Mental Health (S. Listwak, M. Kruesi, P. Gold) Georgetown University Medical Centre (L.Laue).

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