Background/Purpose: Low serum DHEAS may predispose a minority of premenopausal women to RA. A comprehensive panel of serum steroids, their related product-to-precursor (P-P) ratios and pituitary hormones has not been reported in pre-RA vs non-RA control (CN) subjects. This nested case-control prospective study permitted such comparison to assess adrenal and gonadal hormone alterations prior to clinical onset of RA.

Methods: Residents of Washington County, MD (21,061: 12,381 F, 8,680 M) enrolled in the Project CLUE cohort in 1974 and donated serum samples. After 3 to 20 (median 11) years, 54 cohorts were diagnosed ACR-definite RA (36 F, 18 M). Each pre-RA was matched on entry features with 4 non-RA (216 total: 144 F, 72 M) cohort members. Stored (-70 °C) sera were available on most subjects for assays of a comprehensive panel of hormones (15 F, 8 M) by immunoassay methods in a Northwestern University research laboratory. Histograms were compared of pre-RA vs CN hormonal levels and P-P ratios, stratified by entry pre- vs post-menopausal and sex status, to identify range differences (p<0.050). Hormonal correlations were also compared on age-adjusted, log-transformed values by partial Pearson and by Spearman methods. Principal component analysis (PCA) included 8 hormonal values, entry age, sex, and the study group variable (CN vs pre-RA).

Results: In 54 total pre-RA, 6 (11%) had abnormally low cortisol (< 120 nmol/L) levels vs 2 (0.93%) of 215 CN (p = 0.001). The respective P-P ratio of cortisol product to deoxycortisol precursor did not differ between study groups, or the preceding hydroxylated steroid P-P ratios. In females, mean (SEM) androstenedione (Δ4A) level (nmol/L) was 2.01 (0.44) in 28 pre-RA vs 3.52 (0.30) in 108 CN (p = 0.017). The lower Δ4A level in pre-RA was consistent with a lower ratio of < 0.700 for the Δ4A product to 17-OH progesterone precursor, found in 61% of pre-RA vs 34% of CN (p = 0.031). PCA of 11 variables yielded 4 components, explaining 75.2% of total variance: (1) sex and male-related hormones (30.2%); (2) precursor hormones, entry age, and estradiol (25.0%); (3) cortisol (10.5%), and (4) CN vs pre-RA (9.5%).

Conclusion: An excess minority of pre-RA had deficient cortisol levels, females had lower mean androstenedione than CN, and PCA identified cortisol and the CN vs pre-RA variable as independent components, findings which deserve further investigation.