Desmopressin and low-dose ACTH test in rheumatoid arthritis

Abstract

Objective: 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 modi®cations of the steroid milieu are involved. Design: 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. Methods: We studied ten RA patients (39.8 6 7.4 (S.D.) years), de®ned according to the American Rheumatism Association, and seven healthy control patients (34.1 6 9.6 (S.D.) years). All subjects underwent testing, in random order, with placebo, desmopressin (DDAVP) (10 mg i.v.), ovine corticotropin-releasing hormone (oCRH) (1 mg/kg body weight) and low-dose ACTH (5 mg 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). Results: No difference in E2, testosterone or UFC was found between RA patients and controls. IGF-I levels were signi®cantly (P < 0.01) lower in RA patients (110.6 6 6.4 mg/l) than in controls (207.0 6 37.9 mg/l). Mean baseline dehydroepiandrosterone (DHEA) and D4-androstenedione levels of the four tests were signi®cantly (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 À 0.67, P < 0.05) and erythrocyte sedimentation rate (r À 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 signi®cant (P < 0.05) ACTH release was found in controls. Only in RA patients was DDAVP able to induce a signi®cant (P < 0.01) DHEA increase. After oCRH a similar signi®cant 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 signi®cant (P < 0.01) cortisol response was found in both RA patients and controls; indeed in RA patients DHEA AUC (2196.0 6 321.8 nmol/l per 90 min) was signi®cantly lower (P < 0.01) than DHEA AUC (4280.8 6 749.0 nmol/l per 90 min) in controls. A similar signi®cant (P < 0.01), though not abnormal, 17-hydroxyprogesterone response to ACTH was found in both groups. Conclusions: 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 arè normal' but inadequate in the setting of a sustained in¯ammatory disease like RA. The reduced basal and low-dose ACTH-induced DHEA levels could re¯ect 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). Europ...

Lower Serum Androstenedione Levels in Pre-Rheumatoid Arthritis versus Normal Control Women: Correlations with Lower Serum Cortisol Levels

“…In the absence of quantitative measurements of the degree of ACTH, FSH, and LH end-organ stimulation (Figure 2), interpretation of the baseline serum adrenal and sex steroid profiles is challenging in the pre-RA versus CN subjects of this study as well as in previous comparisons of RA patients and controls [4–8, 12, 28–32]. Adrenal cortical stimulation by the insulin-induced hypoglycemia test (IIHT) was studied in pre-menopausal RA patients and control females.…”

“…Significant differences were found only in the 11-deoxy-17-ketosteroid AA steroids: dehydroepiandrosterone (DHEA), androsterone, and etiocholanolone [11]. Subsequent studies of serum DHEA and its sulfate (DHEAS) in early disease premenopausal onset women found lower mean levels of these AA biomarkers than in matched controls [5, 8, 12, 13]. A nested case-control cohort study showed that definitely low baseline serum DHEAS levels (<0.68  μ mol/L), assayed in independent reference laboratories, were present a mean of 11 years before premenopausal onset in 3 (30%) of 10 pre-RA versus 1 (2.7%) of 37 matched CN subjects ( P = 0.026) [14].…”

IGF-I and IGF-I-binding proteins in rats with adjuvant-induced arthritis given recombinant human growth hormone

“…In humans, growth retardation is a serious problem in juvenile chronic arthritis ( JCA). Low levels of IGF-I have been repeatedly reported in JCA and in rheumatoid arthritis (Davies et al 1994, Foppiani et al 1998. Normal and reduced GH secretion have been observed in rheumatoid arthritis (Butenandt et al 1974, Woo 1994.…”

Corticotropin releasing hormone (CRH) promoter polymorphisms in various ethnic groups of patients with rheumatoid arthritis

“…Furthermore, the cortisol response of RA patients to experimental stressors was normal. However, in established RA as well as in RA of recent onset it could be shown that RA patients have an inadequate cortisol production for a given degree of inflammation as well as a loss of circadian rhythm in patients with high disease activity (11,16,24,29). The basis for this deficient cortisol response is not known, but appears not to be a mere consequence of chronic inflammation as it is not seen in patients with osteomyelitis or osteoarthritis.…”

“…Patients with RA have a pattern of disease activity which is dependent on a diurnal rhythm of cortisol secretion but the amount of cortisol secreted is subnormal (11,16,24). Evidence from animal models (28) as well as from studies in RA patients (8) has led to the view that the inadequate cortisol response is due to an insufficient response of the corticotropin releasing hormone (CRH) gene to inflammatory signals.…”