Basal Hypocortisolism

From: <a href="https://www.hindawi.com/journals/isrn/2013/784520/">A Review of Hypothalamic-Pituitary-Adrenal Axis Function in Chronic Fatigue Syndrome</a>

Basal hypocortisolism was first reported in CFS patients in 1981 [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B21">21</a>]. Cortisol concentrations have since been measured in blood, saliva, and urine in a number of studies with rather varying results (reviewed in [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B8">8</a>]), but the notion of a hypocortisolaemic picture in CFS is supported by a meta-analysis [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B22">22</a>]. Reduced cortisol levels are more apparent in female patients and also tend to occur during the later stages of the illness [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B22">22</a>]. These abnormal cortisol concentrations may reflect differences in the biological mediation of the stress response or may be consequent on the differential nature/magnitude of the stressor engendered by the experimental procedure (e.g., the hospital visit or the venepuncture) in patients with CFS compared to comparator subjects [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B8">8</a>, <a href="https://www.hindawi.com/journals/isrn/2013/784520/#B16">16</a>, <a href="https://www.hindawi.com/journals/isrn/2013/784520/#B23">23</a>]. Further, basal studies have also shown an attenuated diurnal variation [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B8">8</a>, <a href="https://www.hindawi.com/journals/isrn/2013/784520/#B24">24</a>] particularly with a loss of the morning peak of ACTH [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B8">8</a>, <a href="https://www.hindawi.com/journals/isrn/2013/784520/#B20">20</a>, <a href="https://www.hindawi.com/journals/isrn/2013/784520/#B21">21</a>, <a href="https://www.hindawi.com/journals/isrn/2013/784520/#B25">25</a>, <a href="https://www.hindawi.com/journals/isrn/2013/784520/#B26">26</a>] or cortisol [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B8">8</a>, <a href="https://www.hindawi.com/journals/isrn/2013/784520/#B20">20</a>, <a href="https://www.hindawi.com/journals/isrn/2013/784520/#B27">27</a>] while challenge studies often, but not invariably, show a diminished HPA axis responsivity. This has been assessed using the ACTH, cortisol, and/or 11-deoxycortisol response to pharmacological challenge using, for example, dexamethasone combined with corticotropin-releasing hormone (CRH) [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B28">28</a>], insulin [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B29">29</a>], inflammatory cytokines, and metyrapone [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B30">30</a>]; to psychological challenge (e.g., using the Trier Social Stress Test [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B31">31</a>]), and to physiological challenge (such as wakening) [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B32">32</a>–<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B34">34</a>].

The hypocortisolaemia, attenuated diurnal variation, and reduced responsivity to challenge seen in these cross-sectional studies may be mediated by upregulation of GR and MR, reduced hormone synthesis, or increased metabolism [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B8">8</a>, <a href="https://www.hindawi.com/journals/isrn/2013/784520/#B35">35</a>]. The enhanced suppression of cortisol during the dexamethasone [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B36">36</a>, <a href="https://www.hindawi.com/journals/isrn/2013/784520/#B37">37</a>] and prednisolone suppression test [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B38">38</a>] supports the notion that increased functional activity of GR and possibly MR may have pathophysiological significance in CFS. However, as dexamethasone is metabolised via cortisol metabolic pathways, the enhanced cortisol suppression during the DST may therefore be caused not by GR upregulation but by reduced dexamethasone metabolism (as a consequence of the enzyme inhibition secondary to persistent hypocortisolaemia [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B39">39</a>]).

The thesis that the hypocortisolaemia is caused by a shift in the balance of the various metabolic pathways (Figure <a href="https://www.hindawi.com/journals/isrn/2013/784520/fig2/" target="_blank">2</a>) in steroid synthesis is tentatively supported but by no means proven by studies examining plasma concentrations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) and by those which calculate the cortisol : DHEA ratio. DHEA levels have been shown to be normal [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B29">29</a>], numerically [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B41">40</a>] or significantly [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B42">41</a>] increased; DHEAS levels have been reported to be reduced [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B43">42</a>, <a href="https://www.hindawi.com/journals/isrn/2013/784520/#B44">43</a>], sand the cortisol : DHEA ratio has been shown to be normal [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B42">41</a>, <a href="https://www.hindawi.com/journals/isrn/2013/784520/#B45">44</a>] or, in the larger study, reduced [<a href="https://www.hindawi.com/journals/isrn/2013/784520/#B41">40</a>] in patients with CFS.