Androgen conversion in osteoarthritis and rheumatoid arthritis synoviocytes – androstenedione and testosterone inhibit estrogen formation and favor production of more potent 5α-reduced androgens

Martin Schmidt,Claudia Weidler,Jürgen Schölmerich,Heidrun Naumann,Rainer H Straub,Sven Anders

doi:10.1186/ar1769

Abstract

In synovial cells of patients with osteoarthritis (OA) and rheumatoid arthritis (RA), conversion products of major anti-inflammatory 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 anti-inflammatory 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.

Highlights

Adrenal and gonadal androgens such as dehydroepiandrosterone (DHEA), androstenedione (ASD), and testosterone have anti-inflammatory properties mediated by blocking the secretion of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF), and other proinflammatory mediators [1,2,3,4,5,6,7]
In a recent preliminary study in mixed synovial cells of three patients with rheumatoid arthritis (RA) and osteoarthritis (OA), we demonstrated that DHEA can be converted to testosterone, estrone (E1), and 17β-estradiol (E2) [17]
Markers of inflammation in synovial tissue In order to delineate severity of local tissue inflammation, we investigated lining layer thickness, overall cellularity, density of CD3+ T cells, CD163+ macrophages, and vascularity

Summary

Introduction

Adrenal and gonadal androgens such as dehydroepiandrosterone (DHEA), androstenedione (ASD), and testosterone have anti-inflammatory properties mediated by blocking the secretion of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF), and other proinflammatory mediators [1,2,3,4,5,6,7]. DHEAS, DHEA, and ASD are the major androgen precursors, which are released from the adrenal gland ( relevant in postmenopausal women). These androgens enter the peripheral cell to be converted to downstream metabolites using diverse enzyme pathways. As a prerequisite for further therapeutic administration of androgens to patients with RA, it is important to know how androgens can be converted into downstream hormones in affected synovial tissue

Results

Discussion

Conclusion