In recent years, a novel and paradoxical phenomenon has emerged from neurobiological studies on the effects of stress. There is increasing evidence for a relatively decreased, rather than an increased, cortisol secretion in individuals who have been exposed to severe stress or suffer from stress-response-related disorders. The phenomenon of hypocortisolism has received growing attention in the field of stress research, inasmuch as it challenges or virtually reverses prevailing concepts on the neuroendocrinology of stress [19
Both fibromyalgia and CFS are often viewed as being stress-response related, and abnormalities of the HPA axis have been found in both disorders. Stress is also known to disrupt the HPG axis, and the characteristic reproductive picture of 'stress'- or exercise-induced amenorrhea is that of infrequent LH pulses despite follicular-phase estradiol and progesterone levels [5
]. Interestingly, abnormalities of the HPA axis reported in other stress-response-related disorders, such as hypothalamic amenorrhea and exercise-induced amenorrhea, involve increased baseline cortisol over 24 hours, whereas previous studies of fibromyalgia and CFS found low cortisol [6
In our study, levels of reproductive HPG axis hormones during the follicular phase showed no significant differences in women with CFS or fibromyalgia from the values in controls. These findings are in agreement with those of Korszun and colleagues [5
], who reported data from nine premenopausal women with fibromyalgia and eight with CFS. They showed no significant differentiations of reproductive axis function in either group of patients with regard to estrogen and progesterone levels and to LH pulsatility during the follicular phase. However, our results are in contradiction to those of Studd and Panay [9
], who reported data from 28 premenopausal women with CFS. Of these, 25% showed low plasma estradiol concentrations. Those authors reported that CFS may represent a hypoestrogenic state and recommended the use of hormone replacement therapy for women with CFS. In addition, they claimed that 80% of patients improved after treatment with estradiol patches and cyclical progestagens. A similar suggestion as to the effect of HRT has been made for women with fibromyalgia by Waxman and Zatskis [10
]. The authors reported estrogen deficit as a prominent promoting factor in the majority of patients with fibromyalgia and recommended estrogen therapy for treatment of fibromyalgia. Further clinical and experimental studies are required to determine the role of sex hormones in the pathogenesis of this condition.
In our study, morning cortisol levels were lower in women with CFS than in healthy controls. Some studies of the HPA axis in CFS show a mild hypocortisolism of central origin, in contrast to hypercortisolism of major depression [21
]. In an early study of the HPA axis in patients with CFS, Demitract and colleagues [6
] reported low 24-hour urine free cortisol compared with that of control subjects. Baseline evening plasma corticotropin levels were elevated and cortisol levels were depressed. Significantly lower baseline cortisol levels were reported in an earlier study [23
]. However, most further studies have failed to replicate those findings. Differences in methodology, and sample characteristics, may explain the variety of results.
Previous studies suggested the existence of perturbation of the HPA axis in fibromyalgia [24
], and a hyper-reactive response of adrenocorticotrophic hormone and GH to various stimuli was detected, whereas in the cortisol response, a decrease occurred [26
]. Crofford [26
] reported elevated serum levels of 24-hour free cortisol, resulting in a loss of normal diurnal cortisol fluctuation, and with stimulation a brisk but lesser increase in cortisol level in fibromyalgia. An earlier study by Griep and colleagues [24
] had found that neither basal levels nor stimulated levels of cortisol differed between groups. In a later study by the same group, mild hypocortisolemia was observed [29
]. Again, differences in methodology, and sample characteristics, may explain the differences in results.
It is known that most patients with fibromyalgia and CFS also have depressive symptoms, and depressive patients suffering from pain are not uncommon. Some investigators have therefore suggested a possible connection between fibromyalgia, CFS, and depression. The first pointer to such a connection is that most patients with fibromyalgia and CFS exhibit depressive symptoms such as fatigue, sleep disturbances, and anxiety [30
]. Second, phenomenological similarities exist between chronic pain syndrome – which has been claimed to be related to depression – and fibromyalgia [31
]. Finally, an increased prevalence of depression has been found in patients with fibromyalgia, and bipolar illness has been diagnosed more frequently in close relatives of such patients [32
]. Similarities in patients with fibromyalgia and depression [33
] raise the possibility of a neuroendocrine relationship between these two disorders. It is unclear whether the depression develops as a reaction to the chronic pain or represents an independent disease within the fibromyalgia [34
In our study, high BDI scores (≥ 17) were detected in 53% and 66%, respectively, of patients with fibromyalgia and CFS. When compared according to score for depressive symptoms, cortisol levels were significantly lower in fibromyalgia patients with high BDI scores than in controls, but not in those with low BDI scores. Cortisol levels in CFS patients with and those without depressive symptoms were significantly lower than in controls, whereas there was no significant difference between fibromyalgia patients with and those without depressive symptoms. In patients without depressive symptoms, cortisol levels were lower in CFS than in fibromyalgia. Comorbid depressive illness is one important confounder present in approximately 50% of CFS patients [35
]. High circulating cortisol is a well-replicated finding in major depression [36
], and so presence of depression makes the cortisol findings more difficult to interpret. Of the 10 subjects studied by Wood and colleagues [37
], 5 had high BDI scores. This may explain their finding of significantly raised baseline cortisol in their sample of CFS patients. Scott and Dinan [22
] reported a finding of low urine free cortisol in patients with CFS compared with healthy controls. In addition, there was no difference in this constituent between depressed and nondepressed patients with CFS. In another study [38
], the same group reported blunted corticotropin and cortisol in response to administration of ovine corticotropin-releasing hormone, without differences in basal levels.
In our study we found that the morning cortisol levels in the fibromyalgia patients with high BDI scores were significantly lower than those with low BDI scores. This is in contradiction to the hypercortisolism of classical major depression. In recent years, however, it has become increasingly apparent that depression is a heterogeneous condition, from both a psychological and a physiological perspective [39
]. Moreover, decreased activity of the HPA axis was reported in some stress-related states such as CFS and atypical and seasonal depression [40
]. Forms of depressive illness dominated by reduced energy, a reactive mood, and a reversal of the typical pattern of vegetative features seen in classical depression have been described [39
]. There may be overlap between symptoms of fibromyalgia and those depressive subtypes or reactive forms of depression in fibromyalgia. This condition may explain the low cortisol levels in patients with fibromyalgia in this study. It may also explain both low morning cortisol in patients with CFS and the lack of abnormalities of hormones of the HPG axis in this study.
This is the first study comparing levels both of hormones of the HPG axis and of cortisol, which is the most important hormone of the HPA axis, in follicular-phase women with fibromyalgia and CFS and evaluating relations between scores for depressive symptoms and the HPG and HPA axes in these patients. Thus, comparison of CFS with fibromyalgia highlights both similarities and differences in neuroendocrinology. It may be that the differences reflect distinct pathophysiologies for the two syndromes. However, the similarities, both in reduced HPA activation, symptomatology, and abrupt stress-related onset, suggest otherwise.
Cortisol levels peak in early morning and need to be collected before patients rise in the morning; and determining single levels of hormones that are secreted in a pulsatile fashion may not be representative of normal functioning. But one should keep in mind that basal hormone levels alone do not reflect activity of the HPA and HPG axes. Sometimes only dynamic (stimulation) tests find differences in the activity of HPA and HPG axes in fibromyalgia. We did not carry out early-morning and repeated measures of these hormones because of the large number of subjects in our study. This point is a limitation of our study.