Foppiani L, Cutolo M, Sessarego P, Sulli A, Prete C, Seriolo B, Giusti M
Cattedra di Endocrinologia, DiSEM, Universita' di Genova, Italy.
Eur J Endocrinol. 1998 Mar;138(3):294-301. doi: 10.1530/eje.0.1380294.
To ascertain whether a different regulation and sensitivity of the hypothalamic-pituitary-adrenal axis exists and whether a type of cortisol resistance is present in rheumatoid arthritis (RA) patients, a chronic disease in whose pathogenesis modifications of the steroid milieu are involved.
We studied the basal and dynamic response of ACTH and adrenal steroids to various stimuli acting on the hypophysis or directly on the adrenal gland.
We studied ten RA patients (39.8 +/- 7.4 (S.D.) years), defined according to the American Rheumatism Association, and seven healthy control patients (34.1 +/- 9.6 (S.D.) years). All subjects underwent testing, in random order, with placebo, desmopressin (DDAVP) (10 microg i.v.), ovine corticotropin-releasing hormone (oCRH) (1 microg/kg body weight) and low-dose ACTH (5 microg i.v.), during the follicular phase of two different menstrual cycles. Blood samples were collected at different times for ACTH and adrenal steroids assay. Baseline estradiol (E2), testosterone and IGF-I levels were also evaluated. All subjects collected urine specimens for 24 h urine free cortisol (UFC).
No difference in E2, testosterone or UFC was found between RA patients and controls. IGF-I levels were significantly (P < 0.01) lower in RA patients (110.6 +/- 6.4 microg/l) than in controls (207.0 +/- 37.9 microg/l). Mean baseline dehydroepiandrosterone (DHEA) and delta4-androstenedione levels of the four tests were significantly (P < 0.05) lower in RA patients than in controls. In RA, a negative correlation was found between mean DHEA levels, class of disease (r = -0.67, P < 0.05) and erythrocyte sedimentation rate (r = -0.63, P < 0.05). After placebo no difference in ACTH and cortisol area under curves (AUCs) was found between RA patients and controls. After DDAVP no cortisol or ACTH response was found in RA patients, while a significant (P < 0.05) ACTH release was found in controls. Only in RA patients was DDAVP able to induce a significant (P < 0.01) DHEA increase. After oCRH a similar significant response in ACTH (P < 0.05), cortisol (P < 0.01), and DHEA (P < 0.01) was found in both groups. After low-dose ACTH, a similar significant (P < 0.01) cortisol response was found in both RA patients and controls; indeed in RA patients DHEA AUC (2196.0 +/- 321.8 nmol/l per 90 min) was significantly lower (P < 0.01) than DHEA AUC (4280.8 +/- 749.0 nmol/l per 90 min) in controls. A similar significant (P < 0.01), though not abnormal, 17-hydroxyprogesterone response to ACTH was found in both groups.
Our study underlines reduced adrenal steroid and IGF-I levels, but not the previously described cortisol resistance in RA patients; it shows that baseline and dynamic cortisol levels are 'normal' but inadequate in the setting of a sustained inflammatory disease like RA. The reduced basal and low-dose ACTH-induced DHEA levels could reflect both a reduced sensitivity of the adrenal gland to exogenous corticotropin and a decreased steroid synthesis due to a partial adrenal enzymatic defect (P450 17,20 lyase).
类风湿关节炎（RA）是一种发病机制涉及类固醇环境改变的慢性疾病，本研究旨在确定RA患者下丘脑 - 垂体 - 肾上腺轴是否存在不同的调节和敏感性，以及是否存在一种皮质醇抵抗类型。
我们研究了促肾上腺皮质激素（ACTH）和肾上腺类固醇对作用于垂体或直接作用于肾上腺的各种刺激的基础和动态反应。
我们研究了10例根据美国风湿病协会定义的RA患者（年龄39.8±7.4（标准差）岁）和7例健康对照患者（年龄34.1±9.6（标准差）岁）。在两个不同月经周期的卵泡期，所有受试者随机接受安慰剂、去氨加压素（DDAVP）（静脉注射10μg）、羊促肾上腺皮质激素释放激素（oCRH）（1μg/kg体重）和低剂量ACTH（静脉注射5μg）测试。在不同时间采集血样用于检测ACTH和肾上腺类固醇。还评估了基线雌二醇（E2）、睾酮和胰岛素样生长因子 - I（IGF - I）水平。所有受试者收集24小时尿标本用于检测尿游离皮质醇（UFC）。
RA患者与对照组在E2、睾酮或UFC方面未发现差异。RA患者的IGF - I水平（110.6±6.4μg/L）显著低于对照组（207.0±37.9μg/L）（P<0.01）。在四项测试中，RA患者的平均基线脱氢表雄酮（DHEA）和Δ4 - 雄烯二酮水平显著低于对照组（P<0.05）。在RA患者中，发现平均DHEA水平与疾病类别（r = -0.67，P<0.05）和红细胞沉降率（r = -0.63，P<0.05）之间呈负相关。给予安慰剂后，RA患者与对照组在ACTH和皮质醇曲线下面积（AUC）方面未发现差异。给予DDAVP后，RA患者未发现皮质醇或ACTH反应，而对照组发现显著的ACTH释放（P<0.05）。仅在RA患者中，DDAVP能够诱导显著的DHEA升高（P<0.01）。给予oCRH后，两组在ACTH（P<0.05）、皮质醇（P<0.01）和DHEA（P<0.01）方面均发现类似的显著反应。给予低剂量ACTH后，RA患者和对照组均发现类似的显著皮质醇反应（P<0.01）；实际上，RA患者的DHEA AUC（2196.0±321.8nmol/L每90分钟）显著低于对照组（4280.8±749.0nmol/L每90分钟）（P<0.01）。两组在对ACTH的17α - 羟孕酮反应方面均发现类似的显著反应（P<0.01），尽管并非异常。
我们的研究强调了RA患者肾上腺类固醇和IGF - I水平降低，但未发现先前描述的皮质醇抵抗；研究表明，基线和动态皮质醇水平是“正常的”，但在像RA这样的持续性炎症疾病背景下是不足的。基础和低剂量ACTH诱导的DHEA水平降低可能既反映了肾上腺对外源性促肾上腺皮质激素的敏感性降低，也反映了由于部分肾上腺酶缺陷（P450 17,20裂解酶）导致的类固醇合成减少。
