RETURN TO TABLE OF CONTENTS
Fall 2001

Neuroenndocrinology, Genetics and Chronic Fatigue Syndrome

By David J. RTorpy, MBBS, PHD, FRACP,
University of Queensland, Australia

Neuroendocrinology focuses on the integrated nervous system and hormone release network that links the brain, pituitary and many endocrine glands. A subset of that network is the stress system, which is composed of the pituitary adrenal axis and sympathetic nervous system and coordinates release of cortisol, norepinephrine and epinephrine in response to acute stressors. These systems may play a role in chronic fatigue syndrome (CFS) and other conditions involving fatigue.

A "stress" can be defined as any influence that may disturb the body's inherent natural balance, including infection, trauma or psychological disturbance such as fear or anxiety. Once the stress system is triggered, a flow of hormones such as cortisol helps the body to defend itself by releasing glucose into the blood, increasing blood pressure and moderating the immune system. 

A number of disorders with fatigue as their hallmark might be related to abnormalities in the stress system. These have been somewhat arbitrarily separated into syndromes such as: idiopathic chronic fatigue (unexplained fatigue for more than six months); CFS (fatigue plus four or more of a group of eight other features, many of which involve pain)¹; and fibromyalgia (pain more prominent than in CFS but frequently associated with fatigue). 

Research findings
Although there is not yet enough evidence to link specific stressors to neuroendocrine problems in CFS and fibromyalgia (FM), there is accumulating evidence of a defect in the stress system in these patients.^2,3 Highlights of current research include:

• Tendency to low cortisol levels in urine and blood
• Shared features with Addison's disease, including fatigue and low blood pressure
• Altered dynamic responses of the stress system, especially cortisol, to stimuli.⁴

However, there have been variable findings. A panel of experts at a March 2001 research symposium on the neuroendocrine aspects of CFS held by The CFIDS Association of America and the U.S. Centers for Disease Control and Prevention (CDC) noted that low cortisol is not consistent in all CFS patients studied. They hypothesized that some of the discrepancy may come from the relapsing-remitting nature of the illness and differing study designs.

It is not known if the hormonal abnormalities identified by researchers reflect the underlying process of CFS or if they contribute directly to symptoms. To help answer this question there have been two treatment trials of hydrocortisone to treat CFS patients.

One positive therapeutic study was conducted in 32 CFS patients with disease duration <100 months and no evidence of major depression or other co-morbid psychiatric disorders. Five mg or 10 mg of hydrocortisone was administered for 28 days in a placebo-controlled design. Approximately 28 percent of patients experienced a reduction in fatigue scores, such that they became comparable to controls. Only nine percent of CFS patients taking placebo experienced similar improvement.⁵

A study of full-replacement level hydrocortisone (approximately 25-35 mg hydrocortisone daily) in 70 CFS patients for three months resulted in slight improvement on symptom scales, particularly in wellness scores, but there was evidence of suppressed adrenocortical responsiveness on the basis of basal and ACTH-stimulated cortisol levels in 12 patients.⁶

The role of genetics
Genetic research may shed some light on the origins of neuroendocrine abnormalities in CFS.
In the last 10 years, studies have described rare genetic mutations of key regulatory components of the stress system, including the glucocorticoid receptor (which "senses" cortisol in the body) and corticosteroid binding globulin (CBG, a transport protein for cortisol), which can lead to CFS-like symptoms.

In the mid-1980s, subjects with altered cortisol receptors were found to have fatigue as their only symptom.^7,8 More recently my research team has discovered a 39-member Italian-Australian family with a newly described loss of function (null) mutation in a gene for CBG, in association with fatigue and relatively low blood pressure.⁹

Plasma CBG was undetectable in family members who are null homozygotes for the mutated CBG gene and reduced by 50 percent of the low-normal range in null heterozygotes. Idiopathic chronic fatigue was present in 12 of 14 adult null heterozygote subjects, and in two of three null homozygotes. Two of the 19 individuals with the null mutation were excluded from assessment for fatigue due to confounding factors related to their associated illnesses.

Significantly, five cases out of the 19 met the CDC criteria for CFS, and other family members had chronic fatigue without associated features, suggesting that these syndromal classifications are not predictive of the mutation. Two other families with milder mutations of the CBG gene, known as the Lyon mutation, have been identified, also in association with fatigue and low blood pressure.^10,11,12

In the case of the family my research team described, investigations were initiated because of a discrepancy between urine and blood cortisol levels - blood cortisol levels were low and urine cortisol levels were normal. However, it would not have been possible to diagnose these patients with biochemical findings alone, if they had only one copy of the CBG null mutation.

It should be noted that although multiple family members with chronic fatigue are often recognized in clinical practice, this does not necessarily imply a common genetic factor, as families tend to share a similar environment. However, studies of identical and non-identical twins with CFS have revealed a genetic component, as the identical twins were more likely to share fatigue symptoms than non-identical twins.^13,14

In addition, as mentioned above, specific mutations in proteins that regulate cortisol transport or action have been found to be associated with fatigue in individual families. It remains to be seen if these alterations of the CBG gene may predispose individuals to the development of CFS.

The mechanism of association between fatigue, relative hypotension and low cortisol has also not been established by these genetic studies. The family we described had lifelong fatigue, albeit variable with time, and did not have postural hypotension. Lack of postural hypotension was also noted in subjects with the glucocorticoid receptor mutation.

Implications for future
There is growing evidence of neuroendocrine disturbances in people with CFS and related disorders. To reinforce this notion, it appears that abnormalities in the proteins for cortisol action or transport may reproduce features of CFS.

In the last 10 years, researchers have discovered specific heritable mutations in cortisol that may lead to fatigue. Although heterogeneity among CFS patient sufferers is the rule, suggesting many potential causes of the illness, the positive findings to date are highly encouraging and should act as an impetus for further work in this field.

It may be that specific "dissection" of the neuroendocrinology of CFS and related disorders may allow us to sub-categorize this enigmatic disease. Such categorization may lead to better diagnosis and treatment of CFS in the not-too-distant future.

1. Fukuda et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med. 1994; 121:953-959.
2. Torpy DJ et al. Chronic fatigue syndrome. www.endotext.org (In press).
3. Torpy DJ et al. Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6 in fibromyalgia: a pilot study. Arthritis and Rheumatism. 2000; 43: 872-880.
4. Demitrack M et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 1991; 73:1224-1234.
5. Cleare AJ et al. Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial. Lancet. 1999; 353:455-458.
6. McKenzie R et al. Low-dose hydrocortisone for treatment of chronic fatigue syndrome. JAMA. 1998; 280:1061-1066.
7. Bronnegard M et al. Primary cortisol resistance associated with a thermolabile glucocorticoid receptor in a patient with fatigue as the only symptom. J Clin Invest. 1986; 78:1270-1278.
8. Chrousos GP et al. Syndromes of glucocorticoid resistance. Ann Intern Med.1993;119:1113-1124.
9. Torpy DJ et al. Familial cortico-steroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension. J Clin Endocrinol Metab. 2001; 86:3692-3700.
10. Emptoz-Bonneton A et al. Novel human corticosteroid-binding globulin variant with low cortisol-binding affinity. J Clin Endocrinol Metab. 2000; 85:361-367.
11. Brunner E et al. Molecular characterization of corticosteroid-binding globulin deficiency in a Brazilian kindred. Endocrine Society Annual Scientific Meeting 2001, Denver CO, poster P1-404. 
12. Baima J et al. Hereditary corticosteroid binding globulin deficiency 
13. Proceedings of the 77th Annual Meeting of the Endocrine Society, Washington DC, 1995, poster 353.
14. Hickie I et al. Unique genetic and environmental determinants of prolonged fatigue: a twin study. Psychol Med. 1999; 29:259-268.
15. Hickie I et al. Complex genetic and environmental relationships between psychological distress, fatigue and immune functioning: a twin study. Psychol Med. 1999; 29:269-277.

Dr. Torpy is a Senior Lecturer in the University of Queens-land Department of Medicine, Greenslopes Private Hospital, Brisbane, Australia. He is the lead author of a study on a newly described genetic mutation that has been associated with fatigue and relative hypotension.