Wilder R L
Inflammatory Joint Diseases Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
J Rheumatol Suppl. 1996 Mar;44:10-2.
Rheumatoid arthritis (RA) is a multifactorial disease in which both environmental and genetic factors play a role. Data also suggest that neuroendocrine factors are involved. I briefly summarize observations that support this hypothesis. RA is characterized by striking age-sex disparities. The incidence of disease in women increases steadily from the age of menarche to its maximal incidence around menopause. The disease is uncommon in men under age 45, but its incidence increases rapidly in older men and approaches the incidence in women. These observations strongly suggest that androgens play a major suppressive role, and, in fact, testosterone levels are depressed in most men with RA. Mechanistically, many data indicate that testosterone suppresses both cellular and humoral immune responses. Dehydroepiandrosterone (DHEA), an adrenal product, is the major androgen in women. Its production is strikingly dependent upon age. Peak production is in the 2nd and 3rd decades, but levels decline precipitously thereafter. DHEA levels are low in both men and women with RA, and recent data show that levels of this hormone may be depressed before the onset of disease. The role of DHEA in immune diseases, however, is controversial. The menopausal peak of RA onset suggests estrogen and/or progesterone deficiency play a role in the disease, and many data indicate that estrogens suppress cellular immunity but stimulate humoral immunity, i.e., deficiency promotes cellular (Th1-type) immunity. Recent data also indicate that progesterone stimulates a switch for Th1 to Th2-type immune responses. RA often develops or flares in the postpartum period, particularly if the mother breastfeeds. This is again consistent with gonadal steroid deficiency playing a role in the onset of disease. Breastfeeding is associated with blunted hypothalamic-pituitary-adrenal function and elevated prolactin synthesis. Gonadal and adrenal steroid hormone deficiency, plus elevated prolactin, probably greatly facilitates the expression of Th1-type immunity, which is widely believed to be critical in the pathogenesis of RA. By contrast, RA typically remits during pregnancy, in parallel with the increasing levels of corticosteroids, estrogens, and progesterone. Pregnancy is characterized by a shift in immune function from Th1-type to Th2-type. Oral contraceptives, which generate a condition of pseudopregnancy, also decrease the risk of RA. These data argue that adrenal and gonadal steroid hormones suppress the development of RA. Several studies indicate that corticosteroid production is inappropriately low in patients with RA, and are reminiscent of observations in Lewis rat models of chronic erosive arthritis. In summary, a growing body of data indicate that RA develops as a consequence of a deficiency in both adrenal and gonadal steroid hormone production. This hypothesis clearly has potential clinical implications.
类风湿关节炎（RA）是一种多因素疾病，环境和遗传因素均在其中发挥作用。数据还表明神经内分泌因素也参与其中。我简要总结支持这一假说的观察结果。RA具有显著的年龄 - 性别差异特征。女性的发病率从初潮年龄开始稳步上升，在绝经前后达到最高发病率。45岁以下男性中该疾病并不常见，但在老年男性中发病率迅速上升并接近女性发病率。这些观察结果强烈表明雄激素起主要抑制作用，事实上，大多数患有RA的男性睾酮水平降低。从机制上讲，许多数据表明睾酮可抑制细胞免疫和体液免疫反应。脱氢表雄酮（DHEA）是一种肾上腺产物，是女性体内主要的雄激素。其分泌显著依赖于年龄。分泌高峰在二三十岁，但此后水平急剧下降。患有RA的男性和女性体内DHEA水平均较低，最近的数据表明在疾病发作前这种激素的水平可能就已降低。然而，DHEA在免疫疾病中的作用存在争议。RA发病的绝经高峰表明雌激素和/或孕激素缺乏在该疾病中起作用，许多数据表明雌激素抑制细胞免疫但刺激体液免疫，即缺乏会促进细胞（Th1型）免疫。最近的数据还表明孕激素刺激Th1向Th2型免疫反应的转变。RA常在产后发病或病情加重，特别是在母亲进行母乳喂养时。这再次表明性腺类固醇缺乏在疾病发作中起作用。母乳喂养与下丘脑 - 垂体 - 肾上腺功能减弱和催乳素合成增加有关。性腺和肾上腺类固醇激素缺乏，加上催乳素升高，可能极大地促进了Th1型免疫的表达，而Th1型免疫被广泛认为在RA的发病机制中起关键作用。相比之下，RA通常在孕期缓解，这与皮质类固醇、雌激素和孕激素水平的升高同时发生。孕期的特点是免疫功能从Th1型向Th2型转变。口服避孕药会产生假孕状态，也会降低患RA的风险。这些数据表明肾上腺和性腺类固醇激素抑制RA的发展。几项研究表明，RA患者的皮质类固醇分泌异常低下，这让人想起慢性侵蚀性关节炎的Lewis大鼠模型中的观察结果。总之，越来越多的数据表明RA是肾上腺和性腺类固醇激素分泌不足的结果。这一假说显然具有潜在的临床意义。
