Castagnetta Luigi A, Carruba Giuseppe, Granata Orazia M, Stefano Rosalba, Miele Monica, Schmidt Martin, Cutolo Maurizio, Straub Rainer H
Department of Experimental Oncology and Clinical Application, University of Palermo, Palermo, Italy.
J Rheumatol. 2003 Dec;30(12):2597-605.
It has been proposed that physiologic levels of estrogens stimulate immune responses whereas androgens suppress inflammatory reactions. Thus, prevalence of synovial androgens relative to estrogens would be favorable in rheumatoid arthritis (RA). We investigated synovial fluid (SF) concentrations of several estrogens and androgens and conversion products of the sex steroid precursor dehydroepiandrosterone (DHEA) in supernatants of mixed synoviocytes.
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).
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 17beta-estradiol (708 pmol/l = 0.193 ng/ml) compared to testosterone (88 pmol/l = 0.026 ng/ml).
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.
有人提出，生理水平的雌激素可刺激免疫反应，而雄激素则抑制炎症反应。因此，类风湿关节炎（RA）患者滑膜中雄激素与雌激素的比例可能更有利于病情。我们研究了混合滑膜细胞上清液中几种雌激素、雄激素以及性类固醇前体脱氢表雄酮（DHEA）的转化产物在滑液（SF）中的浓度。
采用高效液相色谱和质谱法测定12例RA患者和8例膝关节外伤患者（非炎症对照）的滑液类固醇浓度。采用薄层色谱和磷成像检测法，测定3例RA患者和3例骨关节炎（OA）患者中DHEA向下游激素的转化情况。
总体而言，RA患者滑液中游离雌激素的浓度相较于对照组有升高趋势（p < 0.06）。与对照组相比，RA患者滑液中游离雌激素与游离雄激素的摩尔比升高（1.17 ± 0.32 vs 0.29 ± 0.08，无单位；p = 0.017）。RA患者滑液中前体雄烯二酮的游离浓度显著高于对照组（104.6 ± 32.6 vs 30.4 ± 0.4 ng/ml；p = 0.011），且RA患者滑液中雄烯二酮的芳香化酶转化产物雌酮也高于对照组（13.6 ± 2.6 vs 并6.6 ± 0.8 ng/ml；p = 0.035）。与对照组相比，具有生物活性的雌激素衍生物16α - 羟基雌酮和4 - 羟基雌二醇在RA患者中也较高（分别为p = 0.085和p = 0.044）。在混合的RA滑膜细胞中，DHEA转化产生的局部17β -雌二醇水平较高（708 pmol/l = 0.193 ng/ml），而睾酮水平为88 pmol/l = 0.026 ng/ml。
与对照组相比，RA患者滑液中雌激素相对于雄激素的水平显著升高，而雄激素水平则显著降低。这种失衡很可能是由于芳香化酶活性增加所致。因此，一种可用的类固醇前体，如DHEA，可能在滑膜组织中迅速转化为促炎雌激素，进而刺激RA患者的炎症过程。
