A new view on hypocortisolism

Om lavt kortisol-nivå og at det har en beskyttende effekt på kroppen etter langvarig høyt kortisol-nivå. En ny måte å se det på. Det er faktisk en overlevelsesmekanisme. Hvis vi ikke greier å skru av stresset eller fjerne oss fra den stressende livssituasjonen, vil kroppen etter hvert skru av stressresponsen og vi blir oversensitive for enhver utfordring. Utmattelse, muskelsmerter og fibromyalgi blir resultatet. Men likevel er det bedre for organismen enn videre stressresons. Studien forteller hvordan kortisol påvirker sentralnervesystemet, immunsystemet, oppvåkningsresponsen om morgenen, sickness responce, allostatic load, m.m.


Low cortisol levels have been observed in patients with different stress-related disorders such as chronic fatigue syndrome, fibromyalgia, and post- traumatic stress disorder. Data suggest that these disorders are characterized by a symptom triad of enhanced stress sensitivity, pain, and fatigue.

We propose that the phenomenon of hypocortisolism may occur after a prolonged period of hyperactivity of the hypothalamic–pituitary– adrenal axis due to chronic stress as illustrated in an animal model. Further evidence suggests that despite symptoms such as pain, fatigue and high stress sensitivity, hypocortisolism may also have beneficial effects on the organism. This assumption will be underlined by some studies suggesting protective effects of hypocortisolism for the individual.

Since the work of Selye (1936), stress has been associated with an activation of the hypothalamic– pituitary–adrenal (HPA) axis resulting in an increased release of cortisol from the adrenal glands. In recent years, a phenomenon has been described that is characterized by a hyporespon- siveness on different levels of the HPA axis in a number of stress-related states. This phenomenon, termed ‘hypocortisolism’, has been reported in about 20–25% of patients with stress-related dis- orders such as chronic fatigue syndrome (CFS), chronic pelvic pain (CPP), fibromyalgia (FMS), post-traumatic stress disorder (PTSD), irritable bowel syndrome (IBS), low back pain (LBP), burn- out, and atypical depression (Griep et al., 1998; Heim et al., 1998, 2000; Pruessner et al., 1999; Gold and Chrousos, 2002; Gur et al., 2004; Roberts et al., 2004; Rohleder et al., 2004). When hypo- cortisolemic, all these disorders may share affiliated syndromes characterized by a triad of enhanced stress sensitivity, pain, and fatigue.

However, despite different definitions we know today that there is a considerable overlap between the disorders.

In the early 1990s, Hudson and colleagues were amongst the first addressing this issue. They published a study on the comorbidity of FMS with medical and psychiatric disorders in which they reported a higher prevalence of migraine, IBS, and CFS, as well as higher lifetime rates of depression and panic disorder in patients with FMS (Hudson et al., 1992).

Thus, numerous studies on male war veterans have reported an association between PTSD and symp- toms such as fatigue, joint pain, and muscle pain (Engel et al., 2000; Ford et al., 2001).

These alterations of HPA axis are determined by (1) a reduced biosynthesis or release of the respective releasing factor/hormone on different levels of the HPA axis (CRF/AVP from the hypothalamus, ACTH from the pituitary, or cortisol from the adrenal glands) accompanied by a subsequent decreased stimulation of the respective target receptors, (2) a hypersecretion of one secretagogue with a subsequent down-regulation of the respective target receptors, (3) an enhanced sensitivity to the negative feedback of glucocorti- coids, (4) a decreased availability of free cortisol, and/ or (5) reduced effects of cortisol on the target tissue, describing a relative cortisol resistance (Heim et al., 2000; Raison and Miller, 2003).

Several years ago we postulated that hypocortiso- lism/a hyporeactive HPA axis might develop after prolonged periods of stress together with a hyper- activity of the HPA axis and excessive glucocorti- coid release (Hellhammer and Wade, 1993). This proposed time course with changes in HPA axis activity from hyper- to hypocortisolism resembles the history of patients with stress-related disorders who frequently report about the onset of ‘hypo- cortisolemic symptoms’ (fatigue, pain, stress sen- sitivity) after prolonged periods of stress, e.g. work stress, infection, or social stress (Buskila et al., 1998; Van Houdenhove and Egle, 2004)

Thinking about the potential cause/reason for changes in HPA axis activity from hyper- to hypocortisolism one might consider the body’s self-adjusting abilities as an important factor. Self-adjusting abilities play a significant role in survival of the organism by counteracting the enduring increased levels of glucocorticoids, and protecting the organism against the possible dele- terious effects thereof.

Poten- tial mechanisms of the ‘HPA axis adjustment’ are (1) the down-regulation of specific receptors on different levels of the axis (hypothalamus, pitu- itary, adrenals, target cells), (2) reduced biosyn- thesis or depletion at several levels of the HPA axis (CRF, ACTH, cortisol) and/or (3) increased negative feedback sensitivity to glucocorticoids (Hellhammer and Wade, 1993; Heim et al., 2000).

The suppressed stress response after administration of dexamethasone demonstrates an increased sensi- tivity to glucocorticoid negative feedback on the level of the pituitary.

The duration, intensity, number and chronicity of stressors may further pronounce these effects. The low-dose dexamethasone test may be the most sensitive measure of this condition.

The HPA axis plays an important role in the regulation of the SNS. CRF seems to increase the spontaneous discharge rate of locus coeruleus (LC) neurons and enhances norepinephrine (NE) release in the prefrontal cortex (Valentino, 1988; Valentino et al., 1993; Smagin et al., 1995), whereas glucocorticoids seem to exert more inhibitory effects on NE release.

Glucocorticoids are the most potent anti-inflam- matory hormones in the body. They act on the immune system by both suppressing and stimulating pro- and anti-inflammatory mediators. While they promote Th2 development, for example by enhan- cing interleukin (IL)-4 and (IL)-10 secretion by macrophages and Th2 cells (Ramierz et al., 1996), they inhibit inflammatory responses and suppress the production and release of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF- alpha), IL-1 and IL-6 (see Franchimont et al., 2003).

An important role of glucocorticoids during stress is to suppress the production and activity of pro- inflammatory cytokines, thus restraining the inflammatory reaction and preventing tissue destruction (see McEwen et al., 1997; Ruzek et al., 1999; Franchimont et al., 2003).

Therefore, a hypocortisolemic stress response, as observed in patients with stress-related disorders, may result in an overactivity of the immune system in terms of increased inflammatory responses due to impaired suppressive effects of low cortisol levels (see Heim et al., 2000; Rohleder et al., 2004). This assumption is supported by studies reporting elevated levels of pro-inflammatory cytokines in patients with stress-related disorders such as PTSD, CFS, and FMS (Maes et al., 1999; Patarca-Montero et al., 2001; Thompson and Barkhuizen, 2003; Rohleder et al., 2004).

Assessing the cortisol awakening response in pregnant women, preliminary results from our laboratory suggest that women with higher daily stress load showed lower cortisol levels in the morning compared to women with normal to low daily stress load. This result suggests a possible prevention of harmful stimulatory effects of maternal cortisol on placental CRF, which plays a major role in the initiation of delivery (Rieger, 2005).

The term ‘sickness response’ refers to non-specific symptoms such as fatigue, increased pain sensi- tivity, depressed activity, concentration difficul- ties, and anorexia that accompany the response to infection (Hart, 1988; Maier and Watkins, 1998). Sickness behavior at the behavioral level appears to be the expression of a central motivational state that reorganizes the organism’s priority to cope with infectious pathogens (Hart, 1988).

Further evidence for the protective effects of the development of a hypocortisolism refers to the allostatic load index. The term ‘allostatic load’ was irstly introduced by McEwen and Stellar (1993) describing the wear and tear of the body and brain resulting from chronic overactivity or inactivity of physiological systems that are normally involved in adaptation to environmental challenge. Allostatic load results when the allostatic systems (e.g. the HPA axis) are either overworked or fail to shut off after the stressful event is over or when these systems fail to respond adequately to the initial challenge, leading other systems to overreact (McEwen, 1998). In this context, results of Hell- hammer et al. (2004) demonstrate a significantly higher allostatic load index in older compared to younger subjects with the exception of hypocorti- solemic elderly who had a comparable allostatic load to young people even though they scored far higher on perceived stress scales. Considering the fact that allostatic load has been associated with a higher risk for mortality, these data suggest that a hypocortisolemic response to stress may rather be protective than damaging.

Low cortisol levels in the case of pregnant women may protect the mother and the child against the risk of pre-term birth, which could be harmful for both of them. Similarly, low cortisol levels in those individuals who are repeatedly or continuously exposed to intense immune stimuli may be beneficial for health and survival.

Similarly, low cortisol levels in those individuals who are repeatedly or continuously exposed to intense immune stimuli may be beneficial for health and survival. Most strikingly, the demonstration of a low allostatic load index in hypocortisolemic subjects suggests that a down-regulation of the HPA axis in chroni- cally stressed subjects protects those subjects against the harmful effects of a high allostatic load index.

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