Serum adrenal androgens (AAs), including androstenedione (Δ4A) and dehydroepiandrosterone sulfate (DHEAS), have been reported to be lower in female rheumatoid arthritis (RA) patients with early disease. Few data are available on hormonal status of women before the onset of clinical rheumatoid arthritis (pre-RA). A broad baseline panel of serum adrenal and sex steroids was compared in 36 female pre-RA to 144 matched cohort control (CN) subjects to determine differences in their mean values and in patterns of hormonal correlations. Study subjects having lower versus higher baseline serum cortisol levels than the total group's mean value were also analyzed separately to investigate differences in their hormonal levels and correlational patterns. In total subjects, mean (±SE) Δ4A level (nmol/L) was lower ( ) in 28 pre-RA cases ( ) versus 108 CN ( ). The significant ( ) difference was restricted to 9 pre-RA versus 53？CN subjects having lower cortisol levels ( versus ？nmol/L, resp.). In total subjects, no significant difference was found between study subjects in their bivariate correlations of the hormonal panel variables, unlike results found in the subgroups stratified by lower versus higher cortisol levels. A subgroup of pre-RA females may have relative adrenal cortical insufficiency, as reflected by lower Δ4A, especially observed among those subjects with lower cortisol levels. 1. Introduction Relative insufficiency of adrenal glucocorticoid (GC) and androgenic-anabolic (AA) hormones has been suspected to increase the risk of developing rheumatoid arthritis (RA) and to contribute to its multifactorial neuroendocrine immune (NEI) pathogenesis [1–8]. The characteristic age- and sex-specific incidence patterns of RA support a possible constitutional deficiency of adrenal cortical or sex hormones in a subset of susceptible women. The female-to-male (F？:？M) risk ratio of persons developing RA is approximately 2？:？1 during the juvenile and older ages but is significantly increased to about 5？:？1 during the female reproductive years [9]. Of further note, risk of RA onset increases with age in adults, particularly among females. The preceding risk data imply that males have relative protection over females during all ages, but particularly in the younger and middle adult years [9]. A recent study indicated that early age at menopause (≤45 years) was associated with the subsequent risk of developing RA [10]. The hazard remained significant after adjusting for smoking, educational level, and length of breastfeeding [10]. Available data imply that the woman’s risk
References
[1]
A. T. Masi and G. P. Chrousos, “Hypothalamic-pituitary-adrenal-glucocorticoid axis function in rheumatoid arthritis,” The Journal of Rheumatology, vol. 23, no. 4, pp. 577–581, 1996.
[2]
R. L. Wilder, “Adrenal and gonadal steroid hormone deficiency in the pathogenesis of rheumatoid arthritis,” The Journal of Rheumatology, vol. 44, pp. 10–12, 1996.
[3]
R. L. Wilder and I. J. Elenkov, “Hormonal regulation of tumor necrosis factor-α, interleukin-12 and interleukin-10 production by activated macrophages. A disease-modifying mechanism in rheumatoid arthritis and systemic lupus erythematosus?” Annals of the New York Academy of Sciences, vol. 876, pp. 14–31, 1999.
[4]
K. S. Kanik, G. P. Chrousos, H. R. Schumacher, M. L. Crane, C. H. Yarboro, and R. L. Wilder, “Adrenocorticotropin, glucocorticoid, and androgen secretion in patients with new onset synovitis/rheumatoid arthritis: relations with indices of inflammation,” Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 4, pp. 1461–1466, 2000.
[5]
M. Cutolo, L. Foppiani, and F. Minuto, “Hypothalamic-pituitary-adrenal axis impairment in the pathogenesis of rheumatoid arthritis and polymyalgia rheumatica,” Journal of endocrinological investigation, vol. 25, no. 10, pp. 19–23, 2002.
[6]
R. H. Straub, L. Paimela, R. Peltomaa, J. Sch？lmerich, and M. Leirisalo-Repo, “Inadequately low serum levels of steroid hormones in relation to interleukin-6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis,” Arthritis and Rheumatism, vol. 46, no. 3, pp. 654–662, 2002.
[7]
A. T. Masi, J. C. Aldag, and R. T. Chatterton, “Sex hormones and risks of rheumatoid arthritis and developmental or environmental influences,” Annals of the New York Academy of Sciences, vol. 1069, pp. 223–235, 2006.
[8]
R. Imrich, M. Vigas, J. Rovensky, J. C. Aldag, and A. T. Masi, “Adrenal plasma steroid relations in glucocorticoidna？ve premenopausal rheumatoid arthritis patients during insulin-induced hypoglycemia test compared to matched normal control females,” Endocrine Regulations, vol. 43, no. 2, pp. 65–73, 2009.
[9]
A. T. Masi, “Incidence of rheumatoid arthritis: do the observed age-sex interaction patterns support a role of androgenic-anabolic steroid deficiency in its pathogenesis?” British Journal of Rheumatology, vol. 33, no. 8, pp. 697–699, 1994.
[10]
M. Pikwer, U. Bergstr？m, J. A. Nilsson, L. Jacobsson, and C. Turesson, “Early menopause is an independent predictor of rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 71, no. 3, pp. 378–381, 2012.
[11]
A. T. Masi, D. B. Josipovic, and W. E. Jefferson, “Low adrenal androgenic-anabolic steroids in women with rheumatoid arthritis (RA): gas-liquid chromatographic studies of RA patients and matched normal control women indicating decreased 11-deoxy-17-ketosteroid excretion,” Seminars in Arthritis and Rheumatism, vol. 14, no. 1, pp. 1–23, 1984.
[12]
L. Foppiani, M. Cutolo, P. Sessarego et al., “Desmopressin and low-dose ACTH test in rheumatoid arthritis,” European Journal of Endocrinology, vol. 138, no. 3, pp. 294–301, 1998.
[13]
M. Cutolo, L. Foppiani, C. Prete et al., “Hypothalamic-pituitary-adrenocortical axis function in premenopausal women with rheumatoid arthritis not treated with glucocorticoids,” The Journal of Rheumatology, vol. 26, no. 2, pp. 282–288, 1999.
[14]
A. T. Masi, R. T. Chatterton, Y. C. Lu, et al., “Low serum dehydroepiandrosterone sulfate (DHAS) levels, rheumatoid factor (RF) and elevated serum tumor necrosis factor α (TNFα) without cytokine receptor (CK) elevations predict long-term onset of RA in women: a controlled, prospective study,” Arthritis & Rheumatism, vol. 38, p. 214, 1995.
[15]
A. T. Masi, K. B. Elmore, A. A. Rehman, J. C. Aldag, and R. T. Chatterton, “Pre-rheumatoid arthritis (pre-RA) subjects had a minority excess with clearly low serum cortisol levels and females had a lower mean androstenedione levels than control (CN) cohorts in analysis of a large panel of serum steroids and pituitary hormones,” Arthritis & Rheumatism, vol. 64, p. S27, 2012.
[16]
A. T. Masi, A. A. Rehman, K. B. Elmore, and J. C. Aldag, “Serum acute phase protein and inflammatory cytokine network correlations: comparison of a pre-rheumatoid arthritis and non-rheumatoid arthritis community cohort,” Journal of Innate Immunity, vol. 5, no. 2, pp. 100–113, 2013.
[17]
N. C. Vamvakopoulos and G. P. Chrousos, “Hormonal regulation of human corticotropin-releasing hormone gene expression: implications for the stress response and immune/inflammatory reaction,” Endocrine Reviews, vol. 15, no. 4, pp. 409–420, 1994.
[18]
C. R. Parker, R. L. Mixon, R. M. Brissie, and W. E. Grizzle, “Aging alters zonation in the adrenal cortex of men,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 11, pp. 3898–3901, 1997.
[19]
K. J. Helzlsouer, A. J. Alberg, G. B. Gordon, et al., “Serum gonadotropins and steroid hormones and the development of ovarian cancer,” Journal of the American Medical Association, vol. 274, pp. 1926–1930, 1995.
[20]
N. Rothman, K. P. Cantor, A. Blair, et al., “A nested case-control study of non-Hodgkin lymphoma and serum organochlorine residues,” The Lancet, vol. 350, no. 9073, pp. 240–244, 1997.
[21]
A. J. Alberg, G. B. Gordon, S. C. Hoffman, G. W. Comstock, and K. J. Helzlsouer, “Serum dehydroepiandrosterone and dehydroepiandrosterone sulfate and the subsequent risk of developing colon cancer,” Cancer Epidemiology Biomarkers and Prevention, vol. 9, no. 5, pp. 517–521, 2000.
[22]
D. M. Gerlag, K. Raza, L. G. van Baarsen, et al., “EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis,” Annals of the Rheumatic Diseases, vol. 71, no. 5, pp. 638–641, 2012.
[23]
F. C. Arnett, S. M. Edworthy, D. A. Bloch, et al., “The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis,” Arthritis & Rheumatism, vol. 31, no. 3, pp. 315–324, 1988.
[24]
K. T. J？rgensen, A. Wiik, M. Pedersen et al., “Cytokines, autoantibodies and viral antibodies in premorbid and postdiagnostic sera from patients with rheumatoid arthritis: case-control study nested in a cohort of Norwegian blood donors,” Annals of the Rheumatic Diseases, vol. 67, no. 6, pp. 860–866, 2008.
[25]
A. T. Masi, S. L. Feigenbaum, and R. T. Chatterton, “Hormonal and pregnancy relationships to rheumatoid arthritis: convergent effects with immunologic and microvascular systems,” Seminars in Arthritis and Rheumatism, vol. 25, no. 1, pp. 1–27, 1995.
[26]
W. J. Dixon and J. W. Tukey, “Approximate behavior of the distribution of Winsorized t (Trimming/Winsorization 2),” Technometrics, vol. 10, no. 1, pp. 83–98, 1968.
[27]
K. J. Rothman, “No adjustments are needed for multiple comparisons,” Epidemiology, vol. 1, no. 1, pp. 43–46, 1990.
[28]
M. Cutolo, E. Balleari, M. Giusti, M. Monachesi, and S. Accardo, “Sex hormone status of male patients with rheumatoid arthritis: evidence of low serum concentrations of testosterone at baseline and after human chorionic gonadotropin stimulation,” Arthritis and Rheumatism, vol. 31, no. 10, pp. 1314–1317, 1988.
[29]
A. T. Masi, J. A. P. Da Silva, and M. Cutolo, “Perturbations of hypothalamic-pituitary-gonadal (HPG) axis and adrenal androgen (AA) functions in rheumatoid arthritis,” Bailliere's Clinical Rheumatology, vol. 10, no. 2, pp. 295–332, 1996.
[30]
A. T. Masi, R. T. Chatterton, and J. C. Aldag, “Perturbations of hypothalamic-pituitary-gonadal axis and adrenal androgen functions in rheumatoid arthritis: an odyssey of hormonal relationships to the disease,” Annals of the New York Academy of Sciences, vol. 876, pp. 53–63, 1999.
[31]
P. H？rle, G. Pongratz, C. Weidler, R. Büttner, J. Sch？lmerich, and R. H. Straub, “Possible role of leptin in hypoandrogenicity in patients with systemic lupus erythematosus and rheumatoid arthritis,” Annals of the Rheumatic Diseases, vol. 63, no. 7, pp. 809–816, 2004.
[32]
R. Imrich, M. Vlcek, J. C. Aldag et al., “An endocrinologist's view on relative adrenocortical insufficiency in rheumatoid arthritis: annals of the New York Academy of Sciences,” Annals of the New York Academy of Sciences, vol. 1193, pp. 134–138, 2010.
[33]
M. A. Gutiérrez, M. E. García, J. A. Rodriguez, et al., “Hypothalamic-pituitary-adrenal axis function in patients with active rheumatoid arthritis: a controlled study using insulin hypoglycemia stress test and prolactin stimulation,” The Journal of Rheumatology, vol. 26, pp. 277–281, 1999.
[34]
J. Hall, E. F. Morand, S. Medbak et al., “Abnormal hypothalamic-pituitary-adrenal axis function in rheumatoid arthritis: effects of nonsteroidal antiinflammatory drugs and water immersion,” Arthritis and Rheumatism, vol. 37, no. 8, pp. 1132–1137, 1994.
[35]
C. Jorgensen, N. Bressot, C. Bologna, and J. Sany, “Dysregulation of the hypothalamo-pituitary axis in rheumatoid arthritis,” The Journal of Rheumatology, vol. 22, no. 10, pp. 1829–1833, 1995.
[36]
B. Gudbj？rnsson, B. Skogseid, K. ？berg, L. Wide, and R. H？llgren, “Intact adrenocorticotropic hormone secretion but impaired cortisol response in patients with active rheumatoid arthritis. Effect of glucocorticoids,” The Journal of Rheumatology, vol. 23, no. 4, pp. 596–602, 1996.
[37]
E. Templ, M. Koeller, M. Riedl, O. Wagner, W. Graninger, and A. Luger, “Anterior pituitary function in patients with newly diagnosed rheumatoid arthritis,” British Journal of Rheumatology, vol. 35, no. 4, pp. 350–356, 1996.
[38]
L. J. Crofford, K. T. Kalogeras, G. Mastorakos et al., “Circadian relationships between interleukin (IL)-6 and hypothalamic- pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 4, pp. 1279–1283, 1997.
[39]
A. M. M. Eijsbouts, F. H. J. van den Hoogen, R. F. J. M. Laan, A. R. M. M. Hermus, F. C. G. J. Sweep, and L. B. A. van de Putte, “Hypothalamic-pituitary-adrenal axis activity in patients with rheumatoid arthritis,” Clinical and Experimental Rheumatology, vol. 23, no. 5, pp. 658–664, 2005.
[40]
C. C. Chen and C. R. Parker Jr., “Adrenal androgens and the immune system,” Seminars in Reproductive Medicine, vol. 22, no. 4, pp. 369–377, 2004.
[41]
P. J. Hornsby, “Aging of the human adrenal cortex,” Science of Aging Knowledge Environment, vol. 2004, no. 35, p. re6, 2004.
[42]
Y. Nakamura, H. X. Gang, T. Suzuki, H. Sasano, and W. E. Rainey, “Adrenal changes associated with adrenarche,” Reviews in Endocrine and Metabolic Disorders, vol. 10, no. 1, pp. 19–26, 2009.
[43]
P. J. Hornsby, “Adrenarche: a cell biological perspective,” Journal of Endocrinology, vol. 214, pp. 113–119, 2012.
[44]
W. L. Miller, “The syndrome of 17, 20 lyase deficiency,” The Journal of Clinical Endocrinology & Metabolism, vol. 97, no. 1, pp. 59–67, 2012.
[45]
W. L. Miller, “P450 oxidoreductase deficiency: a disorder of steroidogenesis with multiple clinical manifestations,” Science Signaling, vol. 23, no. 254, p. pt11, 2012.
