Hormones

Hydrocortisone/cortisol

In some research35,36 it has been suggested that burnout or chronic fatigue may be a mild form of Addison’s disease (adrenal insufficiency or hypoadrenalism). This is also favoured by the fact that fatigue improves with the supplementation of mineralocorticoids (fludrocortisone) or low-dose hydrocortisone (cortisol). Another study37–39 suggested that CFS may be associated with low serum cortisol and high 5-HT function.

Hydrocortisone treatment in fatigue patients has shown benefit in many studies. In one study, 1 month of low-dose hydrocortisone therapy significantly improved the fatigue of CFS patients (n=32)40. In 28% (n=9) the score became similar to the one of normal subjects. No adrenal suppression occurred in those low-dosed patients (at the insulin tolerance test).

In another similar study41 hydrocortisone-treated patients had a greater improvement in mean wellness score, a greater percentage recording an improvement of 5 or more points in wellness score, and a higher average improvement in wellness score in more days than placebo recipients. (Hydrocortisone 16 mg/m 2 = 20–30 mg at 8am, 5 mg at 2pm over 12 weeks leading 30% net increase in daily cortisol exposure.)

DHEA

In a study by Kuratsune et al42, DHEA was shown to improve energy levels in cases of chronic fatigue. Another study found that DHEA levels were lower in fatigue patients as compared with healthy control subjects. DHEA-S was found to be low in depressed patients. In a similar study43 CFS patients were found to have a blunted serum DHEA response curve after injecting ACTH. This suggests therapeutic as well as diagnostic use of DHEA in fatigue management.

Melatonin

Melatonin, the primary hormone of the pineal gland, maintains normal circadian rhythms. In patients with sleep disorders and altered circadian rhythms, such as jet lag, night shift work, and a variety of neuropsychiatric disorders, oral administration of melatonin can provide the necessary resynchronisation of those cycles. When administered in pharmacological doses, melatonin maintains synchronicity. As the hours of highest melatonin secretion correlate with normal hours of sleep, it has been investigated for use in sleep disorders. Studies have demonstrated that patients with insomnia have decreased nocturnal melatonin secretion.

In a placebo-controlled trial44  of eight subjects with delayed sleep-phase insomnia, it was found that melatonin acts as a ‘phase-setter’ for sleep–wake cycles. Subjects were given placebo or melatonin (5 mg nightly at 10pm) for 4 weeks with a 1-week washout period before crossing to the other treatment, and were allowed to wake naturally. In all subjects, the onset of sleep occurred earlier during melatonin treatment (mean change of 82 minutes; P<0.01); there was also a slight decrease in the total amount of time asleep. Similar results were obtained by another group of researchers who administered 5 mg of melatonin nightly to six subjects with delayed sleep‑phase insomnia. The onset of sleep was an average of 115 minutes earlier when taking melatonin compared with pre-melatonin findings.

Over the past 10 years, a number of randomised, controlled trials support melatonin’s effectiveness for improving aspects of normal sleep.

Management

There are no standard guidelines or set treatment protocols for the management of fatigue. Once the provisional diagnosis is made on the basis of history and exclusion of other possible causes, the management should be started, and should include lifestyle management, cognitive behavioural therapy, sleep hygiene, supervised exercise, and pharmacological support to balance the HPA axis. As the majority of patients complain of fatigue, tiredness and inability to perform day-to-day activities, the management is targeted towards reducing the impact of stress, balancing the energy metabolism, and maintaining the normal levels of neurotransmitters and adrenal hormones.

Conclusions

Stress is inevitable, but the consequences of stress are modifiable if the pathophysiologic basis of effects of stress and fatigue are well understood, and enough education and support is provided to the patient. Fatigue being a subjective feeling is a very hard diagnosis to establish. This leads to a prolonged period of dilemma and delay in treatment. In such scenarios, simply by keeping the point in mind that stress affects the neuroendocrine axis (HPA axis) and preventive and supportive measure targeted towards normalising or balancing the neurotransmitters with lifestyle management, sleep hygiene, balanced nutrition, targeted amino acid precursors and hormones, may significantly reduce the sufferings and improve the quality of life of patients suffering from chronic fatigue.