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

Abstract

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.

Large Scale Metabolic Profiling identifies Novel Steroids linked to Rheumatoid Arthritis

“…16a-OH DHEA is formed by the action of non-specific CYP450 monooxygenases on DHEA but its functions are poorly understood 34 , 35 . The conversion of DHEA to 16a-OH DHEA and its aromatization to 16aOH-estrogens has been demonstrated in synovial cells of patients with RA and osteoarthritis 36 . It may be hypothesized that 16aOH-DHEA is decreased due to lower conversion of DHEAS to DHEA in the synovium of patients with rheumatoid arthritis or due to the depletion of this precursor in the formation of 16a- estrogens, due to increased aromatase activity 37 , 38 .…”

CYB5A polymorphism increases androgens and reduces risk of rheumatoid arthritis in women

“…Instead of enforcing more statistical power by increasing numbers of cases and controls in GWAS, a hypothesis-driven approach combined with functional analyses can help to unravel significant contributions of candidate genes to risk of RA [ 44 ]. RA is associated with comparatively low androgen levels, both systemically and within the inflamed tissue [ 20 , 24 , 25 , 45 , 46 ]. Therefore, we screened the data sets of two published GWAS for polymorphisms in the CYB5A gene [ 31 , 32 ], which is relevant for steroid metabolism and identified two RA-associated SNPs linked to low androgen secretion.…”

“…Correspondingly, the major allele determines lower androgen levels [ 54 ], which precede disease onset in RA patients [ 15 , 16 ]. In addition, local androgen production in the inflamed joints would be hampered by the major allele after disease onset [ 20 , 24 , 25 ].…”

“…Increased estrogen formation and estrogen-to-androgen ratios were found in the synovial fluid of RA patients compared to controls showing increased aromatase activity [ 24 ]. We demonstrated that mixed synoviocytes from patients with RA and osteoarthritis convert DHEA, androstenedione, and testosterone into downstream hormones [ 25 ]. If androgens like testosterone are missing in the tissue, synovial aromatase activity is strongly stimulated, and this leads to a very high synovial estrogen-to-testosterone ratio [ 6 , 25 ].…”

Aromatase deficiency in hematopoietic cells improves glucose tolerance in male mice through skeletal muscle-specific effects

“…Aromatase expression and activity similarly have been demonstrated in hepatocytes, myocytes, and osteoblasts, underscoring the importance of local estrogen production in key metabolic tissues. Notably, immune cells are present in all key metabolic tissues, and aromatase activity has been identified in immune cells including macrophages and both T and B lymphocytes [15][16][17]. Therefore, the possibility exists that aromatase activity within immune cells generates bioactive estrogens that mediate cellintrinsic, intracrine effects, with consequent changes in cellular phenotype and function.…”