Replacement therapy with DHEA plus corticosteroids in patients with chronic inflammatory diseases - substitutes of adrenal and sex hormones

A dysfunction of the hypothalamic - pituitary - adrenal (HPA) axis was foun d in animal models of chronic inflammatory diseases, and the defect was loc ated in more central portions of the HPA axis. This defect of neuroendocrin e regulatory mechanisms contributes to the onset of the model disease. Sinc e these first observations in animal models were made, evidence has accumul ated that the possible defect in the HPA axis in humans is more distal to t he hypothalamus or pituitary gland: In chronic inflammatory diseases, such as rheumatoid arthritis, an alteration of the HPA stress response results i n inappropriately low cortisol secretion in relation to adreno-corticotropi c hormone (ACTH) secretion. Furthermore, it has recently been shown that th e serum levels of another adrenal hormone, dehydroepiandrosterone (DHEA), w ere significantly lower after ACTH stimulation in patients with rheumatoid arthritis without prior corticosteroids than in healthy controls. These stu dies clearly indicate that chronic inflammation alters, particularly, the a drenal response. However, at this point, the reason for the specific altera tion of adrenal function in relation to pituitary function remains to be de termined. Since one of the down-regulated adrenal hormones, DHEA, is an inhibitor of cytokines due to an inhibition of nuclear factor-kappa B (NF-kappaB) activa tion, low levels of this hormone may be deleterious in chronic inflammatory diseases. We have recently demonstrated that DHEA is a potent inhibitor of IL-C, which confirmed an earlier study in mice. Since IL-6 is an important factor for B lymphocyte differentiation, the missing down-regulation of th is cytokine, and others such as TNF, may be a significant risk factor in rh eumatic diseases. Since in these patients, administration of prednisolone o r the chronic inflammatory process itself alters adrenal function, endogeno us adrenal hormones in relation to proinflammatory cytokines change. Furthe rmore, these mechanisms may also lead to shifts in steroidogenesis which ha ve been demonstrated in chronic inflammatory diseases. It was repeatedly de monstrated that the serum level of the sulphated form of DHEA (DHEAS) was s ignificantly lower in patients with chronic inflammatory diseases. Since DH EAS is the pool for peripheral sex steroids, such as testosterone and 17 be ta -estradiol, lack of this hormone leads to a significant sex hormone defi ciency in the periphery. This overview will demonstrate mechanisms why DHEAS is reduced in chronic i nflammatory diseases. The importance of DHEAS deficiency will be demonstrat ed with respect to osteoporosis. As a consequence, we suggest a combined th erapy with corticosteroids plus DHEA in chronic inflammatory diseases.