Cutolo Maurizio, Sulli Alberto, Capellino Silvia, Villaggio Barbara, Montagna Paola, Pizzorni Carmen, Paolino Sabrina, Seriolo Bruno, Felli Lamberto, Straub Rainer H
Research Laboratory and Division of Rheumatology, Department of Internal Medicine-University of Genova, Viale Benedetto XV6, 16132, Genova, Italy.
Ann N Y Acad Sci. 2006 Jun;1069:391-400. doi: 10.1196/annals.1351.037.
Whenever serum estrogen concentrations are normal in rheumatoid arthritis (RA) patients, lower androgen concentrations (i.e., testosterone, androstenedione, and dehydroepiandrosterone sulfate [DHEAS]) are detected in the serum as well as in the synovial fluid of male and female RA patients. The presence in the RA synovial fluid of a significant altered sex hormone balance resulting in lower immunosuppressive androgens and higher immuno-enhancing estrogens, might determine a favorable condition for the development of the immunomediated RA synovitis. The inflammatory cytokines (i.e., TNF-alpha), particularly increased in RA synovitis, are able to markedly stimulate the aromatase activity in peripheral tissues and, therefore, induce the peripheral metabolism from androgens to estrogens. The effects of TNF blockers (and generally of anticytokine agents) on peripheral sex hormone levels seem exerted in a faster way at the level of the RA synovial tissue (before any influence on serum levels) where they seem to block the conversion from androgens (anti-inflammatory) to estrogens (proinflammatory) induced by aromatase. Therefore, the beneficial effects of restoring synovial androgens might be clinically more evident in male RA patients (as recently observed in ANTARES study) since they suffer more for the lack of androgens (anti-inflammatory) on account of the action of TNF-alpha on peripheral hormonal conversion. However, therapy (3 months) with anti-TNF did not change serum levels of typical sex hormones in patients with RA, although baseline values were largely different from controls. In patients with at least long-standing RA, this indicates that alterations of serum sex hormones and altered activity of respective converting enzymes are imprinted for a long-lasting period over at least 12 weeks.
在类风湿关节炎（RA）患者中，无论血清雌激素浓度是否正常，男性和女性RA患者的血清以及滑液中均检测到雄激素浓度较低（即睾酮、雄烯二酮和硫酸脱氢表雄酮 [DHEAS]）。RA滑液中存在显著改变的性激素平衡，导致免疫抑制性雄激素降低而免疫增强性雌激素升高，这可能为免疫介导的RA滑膜炎的发展创造了有利条件。RA滑膜炎中尤其增加的炎性细胞因子（即肿瘤坏死因子-α [TNF-α]）能够显著刺激外周组织中的芳香化酶活性，从而诱导雄激素在外周向雌激素的代谢转化。TNF阻滞剂（以及一般的抗细胞因子药物）对外周性激素水平的影响似乎在RA滑膜组织水平上以更快的方式发挥作用（在对血清水平产生任何影响之前），在该组织中它们似乎阻断了由芳香化酶诱导的雄激素（抗炎）向雌激素（促炎）的转化。因此，恢复滑膜雄激素的有益作用在男性RA患者中可能在临床上更明显（如最近在ANTARES研究中观察到的），因为由于TNF-α对外周激素转化的作用，他们因缺乏雄激素（抗炎）而遭受更多痛苦。然而，抗TNF治疗（3个月）并未改变RA患者典型性激素的血清水平，尽管基线值与对照组有很大差异。对于至少患有长期RA的患者，这表明血清性激素的改变以及相应转化酶活性的改变在至少12周的长时间内持续存在。
