Desmopressin augments pituitary–adrenal responsivity to corticotropin-releasing hormone in subjects with chronic fatigue syndrome and in healthy volunteers

Abstract

Background: Corticotopin-releasing hormone (CRH) and vasopressin (VP) are the two principal neuropeptide regulators of the hypothalamic–pituitary–adrenal axis in man, with VP serving to augment CRH-induced adrenocorticotropic hormone (ACTH) release. Unlike VP, desmopressin (DDAVP), which is a synthetic analogue of VP, when administered alone, has not been shown in healthy subjects to have consistent ACTH-releasing properties. It has been suggested that chronic fatigue syndrome (CFS), characterized by profound fatigue and a constellation of other symptoms, may be caused by a central deficiency of CRH.

Methods: We administered 100 μg ovine CRH (oCRH) and 10 μg DDAVP, both alone and in combination, to a group of subjects with CFS, and to a group of healthy volunteers. Our aim was to establish the effect of DDAVP on CRH-induced ACTH release in these two groups.

Results: The δ-ACTH responses to oCRH were attenuated in the CFS (21.0 ± 4.5 ng/L) compared to the control subjects (57.8 ± 11.0 ng/L; t = 3.2, df = 21, p < .005). The δ-cortisol responses were also reduced in the CFS (157.6 ± 40.7 nmol/L) compared to the healthy subjects (303.5 ± 20.9 nmol/L; t = 3.1, df = 21, p < .01). The δ-ACTH and δ-cortisol responses to DDAVP alone did not differ between the two groups. On administration of both CRH and DDAVP no response differences between the two groups for either ACTH (p = .3) or cortisol output (p = .87) were established. Comparing the ACTH and cortisol responses to CRH and CRH/DDAVP in only those individuals from each group who had both tests, the cortisol output to the combination was significantly greater in the CFS compared to the healthy group. The ACTH output was also increased in the former group, though this was not significant.

Conclusions: DDAVP augments CRH-mediated pituitary–adrenal responsivity in healthy subjects and in patients with CFS. That DDAVP was capable of normalizing the pituitary–adrenal response to oCRH in the CFS group suggests there may be increased vasopressinergic responsivity of the anterior pituitary in CFS and/or that DDAVP may be exerting an effect at an adrenal level.

Introduction

Corticotropin-releasing hormone (CRH) is the primary regulator of the hypothalamic–pituitary–adrenal axis (HPA) in man. Its main companion regulator is vasopressin (VP), a nonapeptide, produced from the parvicelluar neurons of the paraventricular nucleus (PVN), and the magnocellular neurons of the supraoptic nucleus (Antoni 1993). VP plays a role as an adrenocorticotropic hormone (ACTH)-releasing factor at the recently cloned V1b receptor on the anterior pituitary (Sugimoto et al 1994).

Although CRH has been shown to be a more potent secretagogue of ACTH than VP, when VP is administered alone it has significant ACTH-releasing properties in humans Brostoff et al 1968, Salata et al 1988. The coadministration of the two peptides causes an augmented release of ACTH Liu et al 1983, DeBold et al 1984, Lamberts et al 1984; this synergism may be associated with a VP-mediated enhancement of CRH cyclic adenosine monophosphate production at the level of the corticotrope (Giguere et al 1982).

Advances in our understanding of stress physiology have been facilitated by the availability of both ovine and human forms of the neuropeptide CRH as exogenous activators of the HPA. Abnormalities of CRH-induced ACTH release have been demonstrated in a range of psychiatric disorders, including depression Holsboer et al 1984a, Holsboer et al 1984b and anorexia nervosa (Gold et al 1986). VP has been employed clinically to assess the dynamic integrity of the HPA, but its use is limited by its side effects of nausea, abdominal pain, and flushing.

Desmopressin (DDAVP), which has relative specificity for the renal V2 receptor with only mild V1-mediated pressor effects (Sawyer et al 1974), has not been shown to produce a consistent rise in ACTH or cortisol when administered alone to healthy subjects Andersson et al 1972, Malerbi et al 1993, Gaillard et al 1988, Winkelmann et al 1994, Kasagi et al 1994. Both VP and DDAVP can potentiate the response to stimulation with ovine CRH (oCRH) in healthy individuals Favrod-Coune et al 1993, Foppiani et al 1996, Ceserini et al 1997. These studies indicated that DDAVP administration is not associated with the hypotensive effects of VP, rendering it a potentially more satisfactory research and diagnostic tool.

The last decade has seen a surge in interest in HPA functioning in chronic fatigue syndrome (CFS). For a diagnosis of CFS an individual must have severe fatigue of 6 months duration resulting in a reduction in activity levels of over 50%. Four of the following eight symptoms must also be present over this period: recurrent sore throats, enlarged and tender lymph glands, unrefreshing sleep, arthralgia, myalgia, recurrent headaches, postexertional malaise, and neuropsychological complaints (Fukuda et al 1994). Demitrack et al (1991), in a dynamic assessment of the HPA in CFS, demonstrated a blunted ACTH release but normal cortisol release to CRH administration, this occurring in the setting of low circulating cortisol levels. A subsequent study found both reduced ACTH and reduced cortisol responses (Scott et al 1998a) to CRH stimulation. These and other studies pointed to an overall hypofunctioning of the HPA axis in this disorder Bearn et al 1995, Dinan et al 1997.

DDAVP is known not to release ACTH in healthy subjects, yet the data indicate a potentiating effect on CRH-induced ACTH release. Given that blunted ACTH responses to CRH stimulation in CFS subjects have been previously reported, what impact would the administration of both substances have on pituitary–adrenal activation in this disorder? In addressing this question we administered CRH, DDAVP, and DDAVP/CRH combined to a group of healthy subjects and chronic fatigue patients.