Hormonal parameters and sex hormone receptor gene polymorphisms in men with autoimmune diseases
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Abstract
Autoimmune diseases (ADs) are more common in women than in men. Sex hormones may play a role. Sex hormone receptors (SHR) are expressed in cells of the immune system. We investigated the possible role of hormonal parameters and of common polymorphisms of the estrogen receptor alpha (ESR1), beta (ESR2), and androgen receptor (AR) genes in the appearance of AD in men. 277 men were studied; 125 with ≥1 AD: Hashimoto’s autoimmune thyroiditis (n = 65), Graves’ disease (n = 12), SLE (n = 10), and RA (n = 38). 152 were controls. Hormonal and biochemical parameters were measured after discontinuation for ≥1 month of any corticosteroid therapy. ESR1 PvuII, ESR2 AluI, and the AR (CAG)n repeats polymorphisms were analyzed. AD patients had higher estradiol levels (31.32 ± 12.10, controls 20.37 ± 7.91 pg/ml, p < 0.001). In multivariate analysis, significant predictors for AD were estrogen and BMI. The allele frequency of ESR1 PvuII and ESR2 AluI did not differ between patients and controls (AD: 47.8 %, 37.6 %; controls 49.8 %, 39.9 %). The distribution of (CAG)n did not differ between groups. In AD group, shorter (CAG)n alleles were associated with younger age of AD onset (short: 38.52 ± 14.8, long: 47.14 ± 17.34 years, p = 0.048). Carriers of ESR1 PvuII presented less frequently ≥2 AD (carriers 6.5 %, non-carriers 25.1 %, p = 0.019); carriers of AluI had lower SHBG levels and higher ΒΜΙ compared to non-carriers (p < 0.04). Higher estradiol may play a role in AD in men. Distribution of SHR gene polymorphisms is similar between patients and controls. Shorter AR (CAG)n repeats may predispose for younger AD onset. Coexistence of ≥2 AD is less frequent in carriers of ESR1 PvuII. ESR2 AluI may adversely affect obesity parameters.
Keywords
Estrogen Estrogen receptor Androgen Androgen receptor Autoimmune MenReferences
- 1.Bouman A, Heineman MJ, Faas MM (2005) Sex hormones and the immune response in humans. Hum Reprod Update 11(4):411–423. doi: 10.1093/humupd/dmi008 PubMedCrossRefGoogle Scholar
- 2.Cutolo M, Capellino S, Sulli A, Serioli B, Secchi ME, Villaggio B, Straub RH (2006) Estrogens and autoimmune diseases. Ann NY Acad Sci 1089:538–547. doi: 10.1196/annals.1386.043 PubMedCrossRefGoogle Scholar
- 3.Cutolo M, Sulli A, Capellino S, Villaggio B, Montagna P, Seriolo B, Straub RH (2004) Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus 13(9):635–638PubMedCrossRefGoogle Scholar
- 4.Kassi E, Moutsatsou P (2010) Estrogen receptor signaling and its relationship to cytokines in systemic lupus erythematosus. J Biomed Biotechnol 2010:317452. doi: 10.1155/2010/317452 PubMedCrossRefGoogle Scholar
- 5.Cutolo M, Capellino S, Straub RH (2008) Oestrogens in rheumatic diseases: friend or foe? Rheumatology (Oxford) 47 Suppl 3:iii2–5. doi: 10.1093/rheumatology/ken150
- 6.Whitacre CC, Reingold SC, O’Looney PA (1999) A gender gap in autoimmunity. Science 283(5406):1277–1278PubMedCrossRefGoogle Scholar
- 7.Masi AT (2000) Hormonal and immunologic risk factors for the development of rheumatoid arthritis: an integrative physiopathogenetic perspective. Rheum Dis Clin North Am 26(4):775–803PubMedCrossRefGoogle Scholar
- 8.Cutolo M, Straub RH (2009) Insights into endocrine-immunological disturbances in autoimmunity and their impact on treatment. Arthritis Res Ther 11(2):218. doi: 10.1186/ar2630 PubMedCrossRefGoogle Scholar
- 9.Erlandsson MC, Jonsson CA, Islander U, Ohlsson C, Carlsten H (2003) Oestrogen receptor specificity in oestradiol-mediated effects on B lymphopoiesis and immunoglobulin production in male mice. Immunology 108(3):346–351PubMedCrossRefGoogle Scholar
- 10.Karpuzoglu-Sahin E, Zhi-Jun Y, Lengi A, Sriranganathan N, Ansar Ahmed S (2001) Effects of long-term estrogen treatment on IFN-gamma, IL-2 and IL-4 gene expression and protein synthesis in spleen and thymus of normal C57BL/6 mice. Cytokine 14(4):208–217. doi: 10.1006/cyto.2001.0876 PubMedCrossRefGoogle Scholar
- 11.Giltay EJ, Fonk JC, von Blomberg BM, Drexhage HA, Schalkwijk C, Gooren LJ (2000) In vivo effects of sex steroids on lymphocyte responsiveness and immunoglobulin levels in humans. J Clin Endocrinol Metab 85(4):1648–1657PubMedCrossRefGoogle Scholar
- 12.Kassi EN, Vlachoyiannopoulos PG, Moutsopoulos HM, Sekeris CE, Moutsatsou P (2001) Molecular analysis of estrogen receptor alpha and beta in lupus patients. Eur J Clin Invest 31(1):86–93PubMedCrossRefGoogle Scholar
- 13.Alevizaki M, Saltiki K, Cimponeriu A, Kanakakis I, Xita N, Alevizaki CC, Georgiou I, Sarika HL (2007) Severity of cardiovascular disease in postmenopausal women: associations with common estrogen receptor alpha polymorphic variants. Eur J Endocrinol 156(4):489–496. doi: 10.1530/EJE-06-0685 PubMedCrossRefGoogle Scholar
- 14.Shearman AM, Cooper JA, Kotwinski PJ, Miller GJ, Humphries SE, Ardlie KG, Jordan B, Irenze K, Lunetta KL, Schuit SC, Uitterlinden AG, Pols HA, Demissie S, Cupples LA, Mendelsohn ME, Levy D, Housman DE (2006) Estrogen receptor alpha gene variation is associated with risk of myocardial infarction in more than seven thousand men from five cohorts. Circ Res 98(5):590–592. doi: 10.1161/01.RES.0000210578.62102.a6 PubMedCrossRefGoogle Scholar
- 15.Rexrode KM, Ridker PM, Hegener HH, Buring JE, Manson JE, Zee RY (2007) Polymorphisms and haplotypes of the estrogen receptor-beta gene (ESR2) and cardiovascular disease in men and women. Clin Chem 53(10):1749–1756. doi: 10.1373/clinchem.2007.091454 PubMedCrossRefGoogle Scholar
- 16.Ichikawa S, Koller DL, Peacock M, Johnson ML, Lai D, Hui SL, Johnston CC, Foroud TM, Econs MJ (2005) Polymorphisms in the estrogen receptor beta (ESR2) gene are associated with bone mineral density in Caucasian men and women. J Clin Endocrinol Metab 90(11):5921–5927. doi: 10.1210/jc.2004-2253 PubMedCrossRefGoogle Scholar
- 17.Ushiyama T, Mori K, Inoue K, Huang J, Nishioka J, Hukuda S (1999) Association of oestrogen receptor gene polymorphisms with age at onset of rheumatoid arthritis. Ann Rheum Dis 58(1):7–10PubMedCrossRefGoogle Scholar
- 18.Liu ZH, Cheng ZH, Gong RJ, Liu H, Liu D, Li LS (2002) Sex differences in estrogen receptor gene polymorphism and its association with lupus nephritis in Chinese. Nephron 90(2):174–180PubMedCrossRefGoogle Scholar
- 19.Lee YJ, Shin KS, Kang SW, Lee CK, Yoo B, Cha HS, Koh EM, Yoon SJ, Lee J (2004) Association of the oestrogen receptor alpha gene polymorphisms with disease onset in systemic lupus erythematosus. Ann Rheum Dis 63(10):1244–1249. doi: 10.1136/ard.2003.012583 PubMedCrossRefGoogle Scholar
- 20.Kassi E, Vlachoyiannopoulos PG, Kominakis A, Kiaris H, Moutsopoulos HM, Moutsatsou P (2005) Estrogen receptor alpha gene polymorphism and systemic lupus erythematosus: a possible risk? Lupus 14(5):391–398PubMedCrossRefGoogle Scholar
- 21.Johansson M, Arlestig L, Moller B, Smedby T, Rantapaa-Dahlqvist S (2005) Oestrogen receptor alpha gene polymorphisms in systemic lupus erythematosus. Ann Rheum Dis 64(11):1611–1617. doi: 10.1136/ard.2004.032425 PubMedCrossRefGoogle Scholar
- 22.Kisiel B, Bednarczuk T, Kostrzewa G, Kosinska J, Miskiewicz P, Plazinska MT, Bar-Andziak E, Krolicki L, Krajewski P, Ploski R (2008) Polymorphism of the oestrogen receptor beta gene (ESR2) is associated with susceptibility to Graves’ disease. Clin Endocrinol (Oxford) 68(3):429–434. doi: 10.1111/j.1365-2265.2007.03060.x CrossRefGoogle Scholar
- 23.Cutolo M, Seriolo B, Villaggio B, Pizzorni C, Craviotto C, Sulli A (2002) Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis. Ann NY Acad Sci 966:131–142PubMedCrossRefGoogle Scholar
- 24.Olsen NJ, Kovacs WJ (2001) Effects of androgens on T and B lymphocyte development. Immunol Res 23(2–3):281–288. doi: 10.1385/IR:23:2-3:281 PubMedCrossRefGoogle Scholar
- 25.Palazzolo I, Gliozzi A, Rusmini P, Sau D, Crippa V, Simonini F, Onesto E, Bolzoni E, Poletti A (2008) The role of the polyglutamine tract in androgen receptor. J Steroid Biochem Mol Biol 108(3–5):245–253. doi: 10.1016/j.jsbmb.2007.09.016 PubMedCrossRefGoogle Scholar
- 26.Skjaerpe PA, Giwercman YL, Giwercman A, Svartberg J (2010) Androgen receptor gene polymorphism and the metabolic syndrome in 60–80 years old Norwegian men. Int J Androl 33(3):500–506. doi: 10.1111/j.1365-2605.2008.00942.x PubMedCrossRefGoogle Scholar
- 27.Alevizaki M, Cimponeriu AT, Garofallaki M, Sarika HL, Alevizaki CC, Papamichael C, Philippou G, Anastasiou EA, Lekakis JP, Mavrikakis M (2003) The androgen receptor gene CAG polymorphism is associated with the severity of coronary artery disease in men. Clin Endocrinol (Oxford) 59(6):749–755. doi: 10.1046/j.1365-2265.2003.01917.x CrossRefGoogle Scholar
- 28.Hardy DO, Scher HI, Bogenreider T, Sabbatini P, Zhang ZF, Nanus DM, Catterall JF (1996) Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. J Clin Endocrinol Metab 81(12):4400–4405PubMedCrossRefGoogle Scholar
- 29.Davis-Dao CA, Tuazon ED, Sokol RZ, Cortessis VK (2007) Male infertility and variation in CAG repeat length in the androgen receptor gene: a meta-analysis. J Clin Endocrinol Metab 92(11):4319–4326. doi: 10.1210/jc.2007-1110 PubMedCrossRefGoogle Scholar
- 30.Kawasaki T, Ushiyama T, Ueyama H, Inoue K, Mori K, Ohkubo I, Hukuda S (1999) Polymorphic CAG repeats of the androgen receptor gene and rheumatoid arthritis. Ann Rheum Dis 58(8):500–502PubMedCrossRefGoogle Scholar
- 31.Mori K, Ushiyama T, Inoue K, Hukuda S (2000) Polymorphic CAG repeats of the androgen receptor gene in Japanese male patients with ankylosing spondylitis. Rheumatology (Oxford) 39(5):530–532CrossRefGoogle Scholar
- 32.Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31(3):315–324PubMedCrossRefGoogle Scholar
- 33.Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, Schaller JG, Talal N, Winchester RJ (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25(11):1271–1277PubMedCrossRefGoogle Scholar
- 34.Sekigawa I, Fujishiro M, Yamaguchi A, Kawasaki M, Inui A, Nozawa K, Takasaki Y, Takamori K, Ogawa H (2010) A new hypothesis of the possible mechanisms of gender differences in systemic lupus erythematosus. Clin Exp Rheumatol 28(3):419–423PubMedGoogle Scholar
- 35.Weidler C, Harle P, Schedel J, Schmidt M, Scholmerich J, Straub RH (2004) Patients with rheumatoid arthritis and systemic lupus erythematosus have increased renal excretion of mitogenic estrogens in relation to endogenous antiestrogens. J Rheumatol 31(3):489–494PubMedGoogle Scholar
- 36.Cutolo M, Villaggio B, Seriolo B, Montagna P, Capellino S, Straub RH, Sulli A (2004) Synovial fluid estrogens in rheumatoid arthritis. Autoimmun Rev 3(3):193–198. doi: 10.1016/j.autrev.2003.08.003 PubMedCrossRefGoogle Scholar
- 37.Tengstrand B, Carlstrom K, Fellander-Tsai L, Hafstrom I (2003) Abnormal levels of serum dehydroepiandrosterone, estrone, and estradiol in men with rheumatoid arthritis: high correlation between serum estradiol and current degree of inflammation. J Rheumatol 30(11):2338–2343PubMedGoogle Scholar
- 38.Folomeev M, Dougados M, Beaune J, Kouyoumdjian JC, Nahoul K, Amor B, Alekberova Z (1992) Plasma sex hormones and aromatase activity in tissues of patients with systemic lupus erythematosus. Lupus 1(3):191–195PubMedCrossRefGoogle Scholar
- 39.McMurray RW, May W (2003) Sex hormones and systemic lupus erythematosus: review and meta-analysis. Arthritis Rheum 48(8):2100–2110. doi: 10.1002/art.11105 PubMedCrossRefGoogle Scholar
- 40.Castagnetta LA, Carruba G, Granata OM, Stefano R, Miele M, Schmidt M, Cutolo M, Straub RH (2003) Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis. J Rheumatol 30(12):2597–2605PubMedGoogle Scholar
- 41.Heikkila R, Aho K, Heliovaara M, Knekt P, Reunanen A, Aromaa A, Leino A, Palosuo T (1998) Serum androgen-anabolic hormones and the risk of rheumatoid arthritis. Ann Rheum Dis 57(5):281–285PubMedCrossRefGoogle Scholar
- 42.Wang J, Nuite M, McAlindon TE (2010) Association of estrogen and aromatase gene polymorphisms with systemic lupus erythematosus. Lupus 19(6):734–740. doi: 10.1177/0961203309359517 PubMedCrossRefGoogle Scholar
- 43.Lu ZM, Wang ZE, Liu YQ, Wu CX, Wang CY, Zhang BC, Shao S, Jiao YL, Che ZX, Chen ZJ, Zhao YR (2009) Association of estrogen receptor alpha gene polymorphisms with cytokine genes expression in systemic lupus erythematosus. Croat Med J 50(2):117–123PubMedCrossRefGoogle Scholar
- 44.Roselli CE, Resko JA (1997) Sex differences in androgen-regulated expression of cytochrome P450 aromatase in the rat brain. J Steroid Biochem Mol Biol 61(3–6):365–374PubMedCrossRefGoogle Scholar
- 45.Nilsson M, Dahlman I, Jiao H, Gustafsson JA, Arner P, Dahlman-Wright K (2007) Impact of estrogen receptor gene polymorphisms and mRNA levels on obesity and lipolysis—a cohort study. BMC Med Genet 8:73. doi: 10.1186/1471-2350-8-73 PubMedCrossRefGoogle Scholar
- 46.Liang YQ, Akishita M, Kim S, Ako J, Hashimoto M, Iijima K, Ohike Y, Watanabe T, Sudoh N, Toba K, Yoshizumi M, Ouchi Y (2002) Estrogen receptor beta is involved in the anorectic action of estrogen. Int J Obes Relat Metab Disord 26(8):1103–1109. doi: 10.1038/sj.ijo.0802054 PubMedCrossRefGoogle Scholar