Objective. Cortisol, the biologically active glucocorticoid, is a major endogenous antiinflammatory factor in rheumatoid arthritis (RA). The aim of this study was to examine the local conversion of cortisol to biologically inactive cortisone and vice versa (the cortisol-cortisone shuttle) in RA and osteoarthritis (OA) patients.Methods. Thin-layer chromatography and phosphorimaging were used to examine the cortisolcortisone shuttle in mixed synovial cells. Double immunohistochemistry was used to assess the key enzymes 11␤-hydroxysteroid dehydrogenase 1 (11␤-HSD1) and 11␤-HSD2 and their possible cellular locations.Results. Double immunohistochemistry demonstrated 11␤-HSD1/2؉ macrophages in the sublining area. The ratio of 11␤-HSD2؉ cells to 11␤-HSD1؉ cells was significantly higher in RA than in OA patients. Cortisol was converted to inactive cortisone in mixed synovial cells from RA and OA patients, which was largely inhibited by carbenoxolone (11␤-HSD1 and 11␤-HSD2 inhibitor). Using metyrapone to inhibit the 11␤-HSD1 reducing reaction (cortisone 3 cortisol), we demonstrated that the capacity for reactivation of cortisone to cortisol was significantly higher in OA than in RA patients. Although the capacity for the cortisonecortisol shuttle was higher in synovial cells from lessinflamed OA tissue compared with inflamed RA tissue, it was obvious that synovial inflammation in RA, but not OA, was related positively to the reactivation of cortisone. This indicates that in RA, a cause other than typical inflammatory factors inhibits the reactivation of cortisone. Since isoproterenol and adenosine inhibited the cortisol-cortisone shuttle, the loss of sympathetic nerve fibers (loss of ␤-adrenergic agonist and adenosine) may be the missing link that accounts for the increased cortisol-cortisone shuttle in RA.Conclusion. This study demonstrates a reduced capacity for local reactivation of cortisone in RA synovial cells. Since synthetic glucocorticoids also use this reactivation shuttle, the results also apply to therapeutic glucocorticoids. This defective reactivation of cortisone may be an important unrecognized pathophysiologic factor in RA.

The incidence of autoimmune diseases is higher in females than in males. In both sexes, adrenal hormones, that is, glucocorticoids, dehydroepiandrosterone (DHEA), and androgens, are inadequately low in patients when compared to healthy controls. Hormonally active androgens are anti-inflammatory, whereas estrogens are pro-inflammatory. Therefore, the mechanisms responsible for the alterations of steroid profiles in inflammation are of major interest. The local metabolism of androgens and estrogens may determine whether a given steroid profile found in a subject's blood results in suppression or promotion of inflammation. The steroid metabolism in mixed synovial cells, fibroblasts, macrophages, and monocytes was assessed. Major focus was on cells from patients with rheumatoid arthritis (RA), while cells from patients with osteoarthritis served as controls. Enzymes directly or indirectly involved in local sex steroid metabolism in RA are: DHEA-sulfatase, 3beta-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, and aromatase (CYP19), which are required for the synthesis of sex steroids from precursors, 5alpha-reductase and 16alpha-hydroxylase, which can be involved either in the generation of more active steroids or in the pathways leading to depletion of active hormones, and 3alpha-reductase and 7alpha-hydroxylase (CYP7B), which unidirectionally are involved in the depletion of active hormones. Androgens inhibit aromatization in synovial cells when their concentration is sufficiently high. As large amounts of estrogens are formed in synovial tissue, there may be a relative lack of androgens. Production of 5alpha-reduced androgens should increase the local anti-inflammatory activity; however, it also opens a pathway for the inactivation of androgens. The data discussed here suggest that therapy of RA patients may benefit from the use of nonaromatizable androgens and/or the use of aromatase inhibitors.

Effects of the opioid antagonist naloxone on concentrations of LH and FSH in plasma were measured in mares during different stages of the oestrous cycle. During the follicular phase of the cycle, naloxone (300 mg i.v.) had no discernible effects on basal concentrations of LH and FSH. A significant increase in plasma LH (P < 0.01) and FSH (P < 0.05) concentrations was observed after naloxone in mares during the luteal phase. This response was not different between suckled and non-suckled mares. The gonadotrophin-releasing hormone analogue buserelin (0.02 mg i.v.) caused a significant (P < 0.05) LH and FSH release irrespective of the stage of the oestrous cycle and a previous naloxone treatment. The results of this study indicate that endogenous opioid peptides are involved in the inhibition of LH and FSH release during the luteal phase of the oestrous cycle in mares and may partially mediate the suppressive influence of progesterone on gonadotrophin secretion. The opioid-mediated suppression of LH and FSH release does not seem to be affected by suckling.

In synovial cells of patients with osteoarthritis (OA) and rheumatoid arthritis (RA), conversion products of major antiinflammatory androgens are as yet unknown but may be proinflammatory. Therefore, therapy with androgens in RA could be a problem. This study was carried out in order to compare conversion products of androgens in RA and OA synoviocytes. In 26 OA and 24 RA patients, androgen conversion in synovial cells was investigated using radiolabeled substrates and analysis by thin-layer chromatography and HPLC. Aromatase expression was studied by immunohistochemistry. Dehydroepiandrosterone (DHEA) was converted into androstenediol, androstenedione (ASD), 16αOH-DHEA, 7αOH-DHEA, testosterone, estrone (E1), estradiol (E2), estriol (E3), and 16αOH-testosterone (similar in OA and RA). Surprisingly, levels of E2, E3, and 16α-hydroxylated steroids were as high as levels of testosterone. In RA and OA, 5α-dihydrotestosterone increased conversion of DHEA into testosterone but not into estrogens. The second androgen, ASD, was converted into 5α-dihydro-ASD, testosterone, and negligible amounts of E1, E2, E3, or 16αOH-testosterone. 5α-dihydro-ASD levels were higher in RA than OA. The third androgen, testosterone, was converted into ASD, 5α-dihydro-ASD, 5α-dihydrotestosterone, and negligible quantities of E1 and E2. 5α-dihydrotestosterone was higher in RA than OA. ASD and testosterone nearly completely blocked aromatization of androgens. In addition, density of aromatase-positive cells and concentration of released E2, E3, and free testosterone from superfused synovial tissue was similar in RA and OA but estrogens were markedly higher than free testosterone. In conclusion, ASD and testosterone might be favorable antiinflammatory compounds because they decrease aromatization and increase anti-inflammatory 5α-reduced androgens. In contrast, DHEA did not block aromatization but yielded high levels of estrogens and proproliferative 16α-hydroxylated steroids. Androgens were differentially converted to pro-and anti-inflammatory steroid hormones via diverse pathways.

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