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

Hormonersatz mittels DHEA plus Glukokortikoide in der Therapie von Patienten mit chronisch entzündlichen Erkrankungen

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Zusammenfassung

In früheren Studien an Ratten wurde gezeigt, dass eine Dysfunktion der Hypothalamus-Hypophysen-Nebennieren(HHN)-Achse vor allen Dingen im Bereich des Hypothalamus lokalisiert ist (genetisch determinierte inadäquate Sekretion von corticotropin-releasing-hormone). Dieser Defekt trug entscheidend zur Entwicklung einer Modell-Arthritis in diesen Tiermodellen bei. Beim Menschen stellte sich diese Situation allerdings anders dar: hier scheint der Defekt vor allen Dingen im Bereich der Nebenniere lokalisiert zu sein, wodurch es zu einer inadäquat niedrigen Kortisolproduktion bei chronisch entzündlichen Erkrankungen in Relation zum systemischen Entzündungsausmaß kommt. Neben Kortisol ist auch ein anderes adrenales Steroid, das Dehydroepiandrosteron (DHEA), drastisch erniedrigt. Die Ursache für die Störung der adrenalen Steroidproduktion bei rheumatoider Arthritis und anderen chronisch entzündlichen Erkrankungen ist zur Zeit nicht bekannt. Da DHEA sowohl den Tumor-Nekrose-Faktor Alpha (TNFα) als auch Interleukin(IL)-6 in vitro und in vivo hemmen kann, hat dieses adrenale Steroidhormon ebenso wie Kortisol wahrscheinlich eine antiinflammatorische Bedeutung. Die Wirkung des DHEA ist dabei durch eine Hemmung des nukleären Faktors NFκB vermittelt. Desweiteren kann DHEA in peripheren Zellen wie beispielsweise Makrophagen zu antiinflammatorisch wirksamen Geschlechtshormonen wie Testosteron umgewandelt werden. Bei Patienten mit chronisch entzündlichen Erkrankungen ist gerade DHEA deutlich erniedrigt, was durch eine zusätzliche Glukokortikoidtherapie noch verstärkt wird. Dieser Überblick demonstriert, warum gerade die Produktion von DHEA bei chronisch entzündlichen Erkrankungen erniedrigt ist. Die Bedeutung der DHEA-Verarmung wird am Beispiel der Osteoporose demonstriert. Es wird dargestellt, weshalb die parallele Therapie mit Glukokortikoiden plus DHEA eine interessante Therapieoption bei chronisch entzündlichen Erkrankungen darstellt.

Summary

A dysfunction of the hypothalamic - pituitary - adrenal (HPA) axis was found in animal models of chronic inflammatory diseases, and the defect was located in more central portions of the HPA axis. This defect of neuroendocrine regulatory mechanisms contributes to the onset of the model disease. Since these first observations in animal models were made, evidence has accumulated that the possible defect in the HPA axis in humans is more distal to the hypothalamus or pituitary gland: In chronic inflammatory diseases, such as rheumatoid arthritis, an alteration of the HPA stress response results in inappropriately low cortisol secretion in relation to adrenocorticotropic hormone (ACTH) secretion. Furthermore, it has recently been shown that the serum levels of another adrenal hormone, dehydroepiandrosterone (DHEA), were significantly lower after ACTH stimulation in patients with rheumatoid arthritis without prior corticosteroids than in healthy controls. These studies clearly indicate that chronic inflammation alters, particularly, the adrenal response. However, at this point, the reason for the specific alteration of adrenal function in relation to pituitary function remains to be determined.

Since one of the down-regulated adrenal hormones, DHEA, is an inhibitor of cytokines due to an inhibition of nuclear factor-kappa B (NF-κB) activation, low levels of this hormone may be deleterious in chronic inflammatory diseases. We have recently demonstrated that DHEA is a potent inhibitor of IL-6, which confirmed an earlier study in mice. Since IL-6 is an important factor for B lymphocyte differentiation, the missing down-regulation of this cytokine, and others such as TNF, may be a significant risk factor in rheumatic diseases. Since in these patients, administration of prednisolone or the chronic inflammatory process itself alters adrenal function, endogenous adrenal hormones in relation to proinflammatory cytokines change. Furthermore, these mechanisms may also lead to shifts in steroidogenesis which have been demonstrated in chronic inflammatory diseases. It was repeatedly demonstrated that the serum level of the sulphated form of DHEA (DHEAS) was significantly lower in patients with chronic inflammatory diseases. Since DHEAS is the pool for peripheral sex steroids, such as testosterone and 17β-estradiol, lack of this hormone leads to a significant sex hormone deficiency in the periphery.

This overview will demonstrate mechanisms why DHEAS is reduced in chronic inflammatory diseases. The importance of DHEAS deficiency will be demonstrated with respect to osteoporosis. As a consequence, we suggest a combined therapy with corticosteroids plus DHEA in chronic inflammatory diseases.

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  1. Laboratory of Neuroendocrinoimmunology, Department of Internal Medicine I, University Hospital, Franz-Josef-Strauß-Allee 11, D-93042, Regensburg, Germany

    R. H. Straub,  J. Schölmerich &  B. Zietz

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Straub, R.H., Schölmerich, J. & Zietz, B. Replacement therapy with DHEA plus corticosteroids in patients with chronic inflammatory diseases - substitutes of adrenal and sex hormones. Z Rheumatol 59 (Suppl 2), II108–II118 (2000). https://doi.org/10.1007/s003930070004

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