Download PDF
Horm Metab Res 2015; 47(06): 411-417
DOI: 10.1055/s-0034-1395667
Review
© Georg Thieme Verlag KG Stuttgart · New York

Genetics of Neuroendocrine Factors in Rheumatoid Arthritis

M. Mravcova
1   Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia
,
L. Chovanova
1   Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia
2   Center for Molecular Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
,
L. Paulikova
2   Center for Molecular Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
,
M. Vlcek
1   Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia
2   Center for Molecular Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
,
J. Rovensky
3   National Institute of Rheumatic Diseases, Piestany, Slovakia
,
Z. Killinger
4   5th Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia
,
J. Wendl
5   Fidelitas, s.r.o., Rheumatology Out-patient Clinic, Bratislava, Slovakia
,
R. Imrich
1   Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia
2   Center for Molecular Medicine, Slovak Academy of Sciences, Bratislava, Slovakia
› Author Affiliations
Further Information

Publication History

received 11 July 2014

accepted 12 November 2014

Publication Date:
12 December 2014 (online)

Also available at
    Permissions and Reprints

Abstract

Inadequate production of cortisol related to inflammation and decrease in adrenal androgen production are hallmarks of hypothalamic-pituitary-adrenal (HPA)-related endocrine findings in rheumatoid arthritis (RA). In particular, lower dehydroepiandrosterone sulfate (DHEAS) levels were consistently found in a subset of premenopausal RA females. Recently, several new gene variants have been identified in association with serum DHEAS concentrations, such as in SULT2A1 and HHEX genes. These DHEAS-related genes and other variants involved in HPA regulation may play a role in the adrenal androgen deficiency in RA. The aim of our study was to review involvement of genetic mechanisms of HPA regulation, with focus on adrenal androgens, in the context of RA pathophysiology. Although, effects of the DHEAS-related gene variants appear to be relatively small compared to other well-known factors such as age, complex interactions between DHEAS-associated genotypes and adrenal androgen hypofunction phenotype may exist in RA. Further studies analyzing specific neuroendocrine phenotype/genotype in RA are needed.

Key words

dehydroepiandrosterone sulfate - hypothalamic-pituitary-adrenal axis - androgens - gene polymorphism
 

  • References

  • 1 Chrousos GP. Stress and disorders of the stress system. Nat Rev Endocrinol 2009; 5: 374-381
    CrossrefPubMedGoogle Scholar
  • 2 Imrich R. The role of neuroendocrine system in the pathogenesis of rheumatic diseases (minireview). Endocr Regul 2002; 36: 95-106
    PubMedGoogle Scholar
  • 3 Besedovsky H, Sorkin E. Network of immune-neuroendocrine interactions. Clin Exp Immunol 1977; 27: 1-12
    PubMedGoogle Scholar
  • 4 Herrmann M, Scholmerich J, Straub RH. Influence of cytokines and growth factors on distinct steroidogenic enzymes in vitro: a short tabular data collection. Ann N Y Acad Sci 2002; 966: 166-186
    CrossrefPubMedGoogle Scholar
  • 5 Imrich R, Rovensky J. Hypothalamic-pituitary-adrenal axis in rheumatoid arthritis. Rheum Dis Clin North Am 2010; 36: 721-727
    CrossrefPubMedGoogle Scholar
  • 6 Cutolo M, Sulli A, Villaggio B, Seriolo B, Accardo S. Relations between steroid hormones and cytokines in rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis 1998; 57: 573-577
    CrossrefPubMedGoogle Scholar
  • 7 Masi AT, Chatterton RT, Aldag JC. Perturbations of hypothalamic-pituitary-gonadal axis and adrenal androgen functions in rheumatoid arthritis: an odyssey of hormonal relationships to the disease. Ann N Y Acad Sci 1999; 876: 53-62 discussion 62–63
    CrossrefPubMedGoogle Scholar
  • 8 Imrich R, Vlcek M, Aldag JC, Kerlik J, Radikova Z, Rovensky J, Vigas M, Masi AT. An endocrinologist’s view on relative adrenocortical insufficiency in rheumatoid arthritis. Ann N Y Acad Sci 2010; 1193: 134-138
    CrossrefPubMedGoogle Scholar
  • 9 Masi AT, Aldag JC, Chatterton RT. Sex hormones and risks of rheumatoid arthritis and developmental or environmental influences. Ann N Y Acad Sci 2006; 1069: 223-235
    CrossrefPubMedGoogle Scholar
  • 10 Cutolo M, Foppiani L, Prete C, Ballarino P, Sulli A, Villaggio B, Seriolo B, Giusti M, Accardo S. Hypothalamic-pituitary-adrenocortical axis function in premenopausal women with rheumatoid arthritis not treated with glucocorticoids. J Rheumatol 1999; 26: 282-288
    PubMedGoogle Scholar
  • 11 Imrich R, Rovensky J, Malis F, Zlnay M, Killinger Z, Kvetnansky R, Huckova M, Vigas M, Macho L, Koska J. Low levels of dehydroepiandrosterone sulphate in plasma, and reduced sympathoadrenal response to hypoglycaemia in premenopausal women with rheumatoid arthritis. Ann Rheum Dis 2005; 64: 202-206
    CrossrefPubMedGoogle Scholar
  • 12 Masi AT, Aldag JC, Chatterton RT, Adams RF, Kitabchi AE. Adrenal androgen and glucocorticoid dissociation in premenopausal rheumatoid arthritis: a significant correlate or precursor to onset?. Z Rheumatol 2000; 59 (Suppl. 02) II/ 54-61
    CrossrefPubMedGoogle Scholar
  • 13 Fournier C. Where do T cells stand in rheumatoid arthritis?. Joint Bone Spine 2005; 72: 527-532
    CrossrefPubMedGoogle Scholar
  • 14 Cope AP, Schulze-Koops H, Aringer M. The central role of T cells in rheumatoid arthritis. Clin Exp Rheumatol 2007; 25: S4-S11
    PubMedGoogle Scholar
  • 15 Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood 2008; 112: 1557-1569
    CrossrefPubMedGoogle Scholar
  • 16 Miyaura H, Iwata M. Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids. J Immunol 2002; 168: 1087-1094
    CrossrefPubMedGoogle Scholar
  • 17 Hu X, Li WP, Meng C, Ivashkiv LB. Inhibition of IFN-gamma signaling by glucocorticoids. J Immunol 2003; 170: 4833-4839
    CrossrefPubMedGoogle Scholar
  • 18 Bollinger T, Bollinger A, Naujoks J, Lange T, Solbach W. The influence of regulatory T cells and diurnal hormone rhythms on T helper cell activity. Immunology 2010; 131: 488-500
    CrossrefPubMedGoogle Scholar
  • 19 Brattsand R, Linden M. Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies. Aliment Pharmacol Ther 1996; 10 (Suppl. 02) 81-90 discussion 91–92
    PubMedGoogle Scholar
  • 20 Fahey AJ, Robins RA, Kindle KB, Heery DM, Constantinescu CS. Effects of glucocorticoids on STAT4 activation in human T cells are stimulus-dependent. J Leukoc Biol 2006; 80: 133-144
    CrossrefPubMedGoogle Scholar
  • 21 Straub RH, Paimela L, Peltomaa R, Scholmerich J, Leirisalo-Repo M. 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 Rheum 2002; 46: 654-662
    CrossrefPubMedGoogle Scholar
  • 22 Gutierrez MA, Garcia ME, Rodriguez JA, Mardonez G, Jacobelli S, Rivero S. Hypothalamic-pituitary-adrenal axis function in patients with active rheumatoid arthritis: a controlled study using insulin hypoglycemia stress test and prolactin stimulation. J Rheumatol 1999; 26: 277-281
    PubMedGoogle Scholar
  • 23 Foppiani L, Cutolo M, Sessarego P, Sulli A, Prete C, Seriolo B, Giusti M. Desmopressin and low-dose ACTH test in rheumatoid arthritis. Eur J Endocrinol 1998; 138: 294-301
    CrossrefPubMedGoogle Scholar
  • 24 Gudbjornsson B, Skogseid B, Oberg K, Wide L, Hallgren R. Intact adrenocorticotropic hormone secretion but impaired cortisol response in patients with active rheumatoid arthritis. Effect of glucocorticoids. J Rheumatol 1996; 23: 596-602
    PubMedGoogle Scholar
  • 25 Kanik KS, Chrousos GP, Schumacher HR, Crane ML, Yarboro CH, Wilder RL. Adrenocorticotropin, glucocorticoid, and androgen secretion in patients with new onset synovitis/rheumatoid arthritis: relations with indices of inflammation. J Clin Endocrinol Metab 2000; 85: 1461-1466
    PubMedGoogle Scholar
  • 26 Chikanza IC, Petrou P, Kingsley G, Chrousos G, Panayi GS. Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis. Arthritis Rheum 1992; 35: 1281-1288
    CrossrefPubMedGoogle Scholar
  • 27 Eijsbouts A, van den Hoogen F, Laan R, de Waal Malefijt M, Hermus A, Sweep C, de Rooij DJ, van de Putte L. Similar response of adrenocorticotrophic hormone, cortisol and prolactin to surgery in rheumatoid arthritis and osteoarthritis. Br J Rheumatol 1998; 37: 1138-1139
    CrossrefPubMedGoogle Scholar
  • 28 Imrich R, Vigas M, Rovensky J, Aldag JC, Masi AT. Adrenal plasma steroid relations in glucocorticoid-naive premenopausal rheumatoid arthritis patients during insulin-induced hypoglycemia test compared to matched normal control females. Endocr Regul 2009; 43: 65-73
    PubMedGoogle Scholar
  • 29 Imrich R, Vlcek M, Kerlik J, Vogeser M, Kirchhoff F, Penesova A, Radikova Z, Lukac J, Rovensky J. Determinants of adrenal androgen hypofunction in premenopausal females with rheumatoid arthritis. Phys Res 2014; 63: 321-329
    PubMedGoogle Scholar
  • 30 Sternberg EM, Young 3rd WS, Bernardini R, Calogero AE, Chrousos GP, Gold PW, Wilder RL. A central nervous system defect in biosynthesis of corticotropin-releasing hormone is associated with susceptibility to streptococcal cell wall-induced arthritis in Lewis rats. Proc Natl Acad Sci USA 1989; 86: 4771-4775
    CrossrefPubMedGoogle Scholar
  • 31 Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med 1995; 332: 1351-1362
    CrossrefPubMedGoogle Scholar
  • 32 Baerwald CG, Mok CC, Tickly M, Lau CS, Wordsworth BP, Ollier B, Panayi GS, Lanchbury JS. Corticotropin releasing hormone (CRH) promoter polymorphisms in various ethnic groups of patients with rheumatoid arthritis. Z Rheumatol 2000; 59: 29-34
    CrossrefPubMedGoogle Scholar
  • 33 Gonzalez-Gay MA, Hajeer AH, Garcia-Porrua C, Dababneh A, Amoli MM, Botana MA, Thomson W, Llorca J, Ollier WE. Corticotropin-releasing hormone promoter polymorphisms in patients with rheumatoid arthritis from northwest Spain. J Rheumatol 2003; 30: 913-917
    PubMedGoogle Scholar
  • 34 Manenschijn L, van den Akker EL, Lamberts SW, van Rossum EF. Clinical features associated with glucocorticoid receptor polymorphisms. An overview. Ann N Y Acad Sci 2009; 1179: 179-198
    CrossrefPubMedGoogle Scholar
  • 35 Koper JW, van Rossum EF, van den Akker EL. Glucocorticoid receptor polymorphisms and haplotypes and their expression in health and disease. Steroids 2014; Aug 20. pii: S0039-128X(14)00206-2 DOI: 10.1016/j.steroids.2014.07.015. [Epub ahead of print]
    PubMedGoogle Scholar
  • 36 van Rossum EF, Koper JW, van den Beld AW, Uitterlinden AG, Arp P, Ester W, Janssen JA, Brinkmann AO, de Jong FH, Grobbee DE, Pols HA, Lamberts SW. Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index. Clin Endocrinol (Oxf) 2003; 59: 585-592
    CrossrefPubMedGoogle Scholar
  • 37 Huizenga NA, Koper JW, De Lange P, Pols HA, Stolk RP, Burger H, Grobbee DE, Brinkmann AO, De Jong FH, Lamberts SW. A polymorphism in the glucocorticoid receptor gene may be associated with and increased sensitivity to glucocorticoids in vivo. J Clin Endocrinol Metab 1998; 83: 144-151
    CrossrefPubMedGoogle Scholar
  • 38 van Rossum EF, Koper JW, Huizenga NA, Uitterlinden AG, Janssen JA, Brinkmann AO, Grobbee DE, de Jong FH, van Duyn CM, Pols HA, Lamberts SW. A polymorphism in the glucocorticoid receptor gene, which decreases sensitivity to glucocorticoids in vivo, is associated with low insulin and cholesterol levels. Diabetes 2002; 51: 3128-3134
    CrossrefPubMedGoogle Scholar
  • 39 van den Akker EL, Russcher H, van Rossum EF, Brinkmann AO, de Jong FH, Hokken A, Pols HA, Koper JW, Lamberts SW. Glucocorticoid receptor polymorphism affects transrepression but not transactivation. J Clin Endocrinol Metab 2006; 91: 2800-2803
    CrossrefPubMedGoogle Scholar
  • 40 Rosmond R, Chagnon YC, Chagnon M, Perusse L, Bouchard C, Bjorntorp P. A polymorphism of the 5'-flanking region of the glucocorticoid receptor gene locus is associated with basal cortisol secretion in men. Metabolism 2000; 49: 1197-1199
    CrossrefPubMedGoogle Scholar
  • 41 van Rossum EF, Roks PH, de Jong FH, Brinkmann AO, Pols HA, Koper JW, Lamberts SW. Characterization of a promoter polymorphism in the glucocorticoid receptor gene and its relationship to three other polymorphisms. Clin Endocrinol (Oxf) 2004; 61: 573-581
    CrossrefPubMedGoogle Scholar
  • 42 Donn R, Payne D, Ray D. Glucocorticoid receptor gene polymorphisms and susceptibility to rheumatoid arthritis. Clin Endocrinol (Oxf) 2007; 67: 342-345
    CrossrefPubMedGoogle Scholar
  • 43 Derijk RH. Single nucleotide polymorphisms related to HPA axis reactivity. Neuroimmunomodulation 2009; 16: 340-352
    CrossrefPubMedGoogle Scholar
  • 44 van Oosten MJ, Dolhain RJ, Koper JW, van Rossum EF, Emonts M, Han KH, Wouters JM, Hazes JM, Lamberts SW, Feelders RA. Polymorphisms in the glucocorticoid receptor gene that modulate glucocorticoid sensitivity are associated with rheumatoid arthritis. Arthritis Res Ther 2010; 12: R159
    CrossrefPubMedGoogle Scholar
  • 45 van den Akker EL, Koper JW, van Rossum EF, Dekker MJ, Russcher H, de Jong FH, Uitterlinden AG, Hofman A, Pols HA, Witteman JC, Lamberts SW. Glucocorticoid receptor gene and risk of cardiovascular disease. Arch Intern Med 2008; 168: 33-39
    CrossrefPubMedGoogle Scholar
  • 46 Miller WL. Disorders of androgen synthesis – from cholesterol to dehydroepiandrosterone. Med Princ Pract 2005; 14 (Suppl. 01) 58-68
    PubMedGoogle Scholar
  • 47 Huang J, Ushiyama T, Inoue K, Mori K, Hukuda S. Possible association of CYP17 gene polymorphisms with the onset of rheumatoid arthritis. Clin Exp Rheumatol 1999; 17: 721-724
    PubMedGoogle Scholar
  • 48 Lo SF, Huang CM, Lin HC, Tsai CH, Tsai FJ. Association of CYP17 gene polymorphism and rheumatoid arthritis in Chinese patients in central Taiwan. Rheumatol Int 2005; 25: 580-584
    CrossrefPubMedGoogle Scholar
  • 49 Lobo RA, Paul WL, Goebelsmann U. Dehydroepiandrosterone sulfate as an indicator of adrenal androgen function. Obstet Gynecol 1981; 57: 69-73
    PubMedGoogle Scholar
  • 50 Rainey WE, Carr BR, Sasano H, Suzuki T, Mason JI. Dissecting human adrenal androgen production. Trends Endocrinol Metab 2002; 13: 234-239
    CrossrefPubMedGoogle Scholar
  • 51 Labrie F. Intracrinology. Mol Cell Endocrinol 1991; 78: C113-C118
    CrossrefPubMedGoogle Scholar
  • 52 Straub RH, Konecna L, Hrach S, Rothe G, Kreutz M, Scholmerich J, Falk W, Lang B. Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence. J Clin Endocrinol Metab 1998; 83: 2012-2017
    CrossrefPubMedGoogle Scholar
  • 53 Cutolo M. Do sex hormones modulate the synovial macrophages in rheumatoid arthritis?. Ann Rheum Dis 1997; 56: 281-284
    CrossrefPubMedGoogle Scholar
  • 54 Pikwer M, Bergstrom U, Nilsson JA, Jacobsson L, Turesson C. Early menopause is an independent predictor of rheumatoid arthritis. Ann Rheum Dis 2012; 71: 378-381
    PubMedGoogle Scholar
  • 55 Kanik KS, Wilder RL. Hormonal alterations in rheumatoid arthritis, including the effects of pregnancy. Rheum Dis Clin North Am 2000; 26: 805-823
    CrossrefPubMedGoogle Scholar
  • 56 Deighton CM, Watson MJ, Walker DJ. Sex hormones in postmenopausal HLA-identical rheumatoid arthritis discordant sibling pairs. J Rheumatol 1992; 19: 1663-1667
    PubMedGoogle Scholar
  • 57 Masi AT, Elmore KB, Rehman AA, Chatterton RT, Goertzen NJ, Aldag JC. Lower Serum Androstenedione Levels in Pre-Rheumatoid Arthritis versus Normal Control Women: Correlations with Lower Serum Cortisol Levels. Autoimmune Dis 2013; 593493
    PubMedGoogle Scholar
  • 58 Heikkila R, Aho K, Heliovaara M, Knekt P, Reunanen A, Aromaa A, Leino A, Palosuo T. Serum androgen-anabolic hormones and the risk of rheumatoid arthritis. Ann Rheum Dis 1998; 57: 281-285
    CrossrefPubMedGoogle Scholar
  • 59 Karlson EW, Chibnik LB, McGrath M, Chang SC, Keenan BT, Costenbader KH, Fraser PA, Tworoger S, Hankinson SE, Lee IM, Buring J, De Vivo I. A prospective study of androgen levels, hormone-related genes and risk of rheumatoid arthritis. Arthritis Res Ther 2009; 11: R97
    CrossrefPubMedGoogle Scholar
  • 60 Zhai G, Teumer A, Stolk L, Perry JR, Vandenput L, Coviello AD, Koster A, Bell JT, Bhasin S, Eriksson J, Eriksson A, Ernst F, Ferrucci L, Frayling TM, Glass D, Grundberg E, Haring R, Hedman AK, Hofman A, Kiel DP, Kroemer HK, Liu Y, Lunetta KL, Maggio M, Lorentzon M, Mangino M, Melzer D, Miljkovic I, Nica A, Penninx BW, Vasan RS, Rivadeneira F, Small KS, Soranzo N, Uitterlinden AG, Volzke H, Wilson SG, Xi L, Zhuang WV, Harris TB, Murabito JM, Ohlsson C, Murray A, de Jong FH, Spector TD, Wallaschofski H. Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms. PLoS Genet 2011; 7: e1002025
    CrossrefPubMedGoogle Scholar
  • 61 Chovanova L, Mravcova M, Imrich R, Rovensky J, Paulikova L, Rakicka M, Marko A, Penesova A, Radner H, Steiner G, Smolen J, Vlcek M. DHEAS-associated genotypes contribute to adrenal androgen hypofunction in RA. Ann Rheum Dis 2014; 73: 349
    CrossrefPubMedGoogle Scholar
  • 62 Dreyer SD, Zheng Q, Zabel B, Winterpacht A, Lee B. Isolation, characterization, and mapping of a zinc finger gene, ZFP95, containing both a SCAN box and an alternatively spliced KRAB A domain. Genomics 1999; 62: 119-122
    CrossrefPubMedGoogle Scholar
  • 63 Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S, Balkau B, Heude B, Charpentier G, Hudson TJ, Montpetit A, Pshezhetsky AV, Prentki M, Posner BI, Balding DJ, Meyre D, Polychronakos C, Froguel P. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007; 445: 881-885
    CrossrefPubMedGoogle Scholar
  • 64 Welch MD, DePace AH, Verma S, Iwamatsu A, Mitchison TJ. The human Arp2/3 complex is composed of evolutionarily conserved subunits and is localized to cellular regions of dynamic actin filament assembly. J Cell Biol 1997; 138: 375-384
    CrossrefPubMedGoogle Scholar
  • 65 Masi AT, Rehman AA, Cutolo M, Aldag JC. Do women with premenopausal-onset rheumatoid arthritis have relative insufficiency or imbalance of adrenocortical steroids?. Ann N Y Acad Sci 2014; 1317: 7-16
    CrossrefPubMedGoogle Scholar
  • 66 Straub RH, Harle P, Yamana S, Matsuda T, Takasugi K, Kishimoto T, Nishimoto N. Anti-interleukin-6 receptor antibody therapy favors adrenal androgen secretion in patients with rheumatoid arthritis: a randomized, double-blind, placebo-controlled study. Arthritis Rheum 2006; 54: 1778-1785
    CrossrefPubMedGoogle Scholar