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

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 [1-7]. The more potent, pure androgen 5α-dihydrotestosterone has been found to repress the NFκB-mediated activation of the human IL-6 gene promoter in human fibroblasts [8], and it also inhibits T cell proliferation [9]. An open, double-blind therapy study with testosterone demonstrated remarkable benefits in patients with RA [10,11]. 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.Apart from gonadal cells, different peripheral cells are able to convert androgens into downstream steroid hormone products such as estrogens [12-16]. Figure 1 demonstrates the complexity of intracellular steroid hormone conversion (intracrinology). 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]. In collagen type II arthritic animals, others have demonstrated that DHEA can be converted into the proinflammatory steroid hormone 7αOH-DHEA, due to increased expression of the P450 enzyme CYP7B [18]. This has been confirmed in RA synovial fibroblasts (J Dulos, personal communication). However, unlike in the case of DHEA, it is presently unknown how ASD and testosterone can be converted into downstream hormones in mixed synovial cells of patients with RA, and whether this conversion is different in OA patients. This is important to know because the delta 4 androgens ASD and testosterone are more potent and, thus, may be used in clinical trials in patients with RA [10,11]. If ASD and testosterone are