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Increased Estrogen Formation and Estrogen to Androgen Ratio in the Synovial Fluid of Patients
with Rheumatoid Arthritis
LUIGI A. CASTAGNETTA, GIUSEPPE CARRUBA, ORAZIA M. GRANATA, ROSALBA STEFANO, MONICA MIELE, MARTIN SCHMIDT, MAURIZIO CUTOLO, and RAINER H. STRAUB
ABSTRACT. Methods. SF steroid concentrations were measured by high performance liquid chromotography and mass spectrometry in 12 patients with RA and 8 subjects with traumatic knee injury (noninflammatory controls). Conversion of DHEA to downstream hormones was measured by thin-layer chromatography and phosphorimaging detection in 3 patients with RA and 3 patients with osteoarthritis (OA). Results. Overall, SF concentration of free estrogens tended to be higher in RA patients versus controls (p < 0.06). Molar ratio of free SF estrogens/free SF androgens was elevated in RA compared to controls (1.17 ± 0.32 vs 0.29 ± 0.08, without unit; p = 0.017). The free SF concentration of the precursor androstenedione was significantly higher in RA patients than in controls (104.6 ± 32.6 vs 30.4 ± 0.4 ng/ml; p = 0.011), and SF estrone — the aromatase conversion product of androstenedione — was also elevated in RA compared to controls (13.6 ± 2.6 vs 6.6 ± 0.8 ng/ml; p = 0.035). The biologically active estrogen derivatives, 16a-hydroxyestrone and 4-hydroxyestradiol, were both higher in RA compared to controls (p = 0.085 and p = 0.044, respectively). In mixed RA synoviocytes, DHEA conversion yielded high local levels of 17ß-estradiol (708 pmol/l = 0.193 ng/ml) compared to testosterone (88 pmol/l = 0.026 ng/ml). Conclusion. SF levels of estrogens relative to androgens are significantly elevated, while those of androgens are markedly reduced, in patients with RA compared to controls. This imbalance is most probably due to increased aromatase activity. Thus, an available steroid precursor, such as DHEA, may be rapidly converted to proinflammatory estrogens in the synovial tissue, which may in turn stimulate the inflammatory process in patients with RA. (J Rheumatol 2003;30:2597-605) Key Indexing Terms:
RHEUMATOID ARTHRITIS
From the Department of Experimental Oncology and Clinical Application, University of Palermo; the Department of Clinical Oncology M. Ascoli, Arnas, Palermo, Italy; Department of Biochemistry II, University Hospital of Friedrich-Schiller University, Jena, Germany; Division of Rheumatology, Department of Internal Medicine, University of Genova, Italy; and the Laboratory of Neuroendocrinoimmunology, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany. Funded by the Italian Association for Cancer Research, Italian Ministry of the University and Research, and the Deutsche Forschungsgemeinschaft (Str 511/10-1; Schm 1611/1-1), and by the respective institutions. L.A. Castagnetta, BSc, PhD, Professor; G. Carruba, MD, PhD, Department of Experimental Oncology and Clinical Application, University of Palermo; O.M. Granata, BSc, Department of Clinical Oncology M. Ascoli; R. Stefano, MD, Department of Experimental Oncology and Clinical Application, University of Palermo; M. Miele, BSc, Department of Clinical Oncology M. Ascoli; M. Schmidt, PhD, Department of Biochemistry II, University Hospital of the Friedrich-Schiller University Jena; M. Cutolo, MD, Professor of Medicine, Division of Rheumatology, Department of Internal Medicine, University of Genova; R.H. Straub, MD, Professor of Experimental Medicine, Department of Internal Medicine I, University Hospital Regensburg. Address reprint requests to Dr. R.H. Straub, Department of Internal Medicine I, Laboratory of Neuroendocrinoimmunology, University Medical Center, D-93042 Regensburg, Germany. E-mail rainer.straub@klinik.uni-regensburg.de Submitted October 30, 2002; revision accepted May 28, 2003.
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