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Autoimmunity, dehydroepiandrosterone (DHEA), and stress

  • Kenneth E Schwartz
    Correspondence
    Address correspondence to: Kenneth E. Schwartz, M.D., Genelabs Technologies, Inc., 505 Penobscot Drive, Redwood City, CA 94063 USA
    Footnotes
    Affiliations
    Genelabs Technologies, Inc., Redwood City, California, USA
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  • Author Footnotes
    1 Dr. Schwartz is an employee of Genelabs Technologies, Inc. which is sponsoring clinical trials on the use of oral prasterone (DHEA) for treatment of systemic lupus erythematosus.
      Steroids secreted by the adult adrenal cortex have been generally classified as mineralocorticoids, glucocorticoids, and androgenic steroids. Although the diverse effects of glucocorticoids on the immune system are well-recognized, attention is beginning to focus on the potential role of androgenic steroids as immunomodulators. This paper will primarily focus on some of the recent advances in our understanding of interactions between adrenal androgenic steroids and the immune system.

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      References

        • De Peretti E.
        • Forest M.G.
        Unconjugated dehydroepiandrosterone plasma levels in normal subjects from birth to adolescence in human.
        J Clin Endocrinol Metab. 1976; 43: 982-991
        • Parker L.N.
        Control of adrenal androgen secretion.
        Endocrinol Metab Clin North Am. 1991; 20: 401-421
        • Gell J.S.
        • Carr B.R.
        • Sasano H.
        • et al.
        Adrenarche results from development of a 3beta-hydroxysteroid dehydrogenase-deficient adrenal reticularis.
        J Clin Endocrinol Metab. 1998; 83: 3695-3701
        • Nakajin S.
        • Shively J.E.
        • Yuan P.M.
        • et al.
        Microsomal cytochrome P-450 from neonatal pig testis.
        Biochemistry. 1981; 20: 4037-4042
        • Geller D.H.
        • Auchus R.J.
        • Mendonca B.B.
        • et al.
        The genetic and functional basis of isolated 17,20-lyase deficiency.
        Nat Genet. 1997; 17: 201-205
        • Miller W.L.
        Early steps in androgen biosynthesis.
        Bailliere’s Clin Endocrinol Metab. 1998; 12: 67-81
        • Garcia-Mayor R.V.
        • Andrade M.A.
        • Rios M.
        • et al.
        Serum leptin levels in normal children.
        J Clin Endocrinol Metab. 1997; 82: 2849-2855
        • Blum W.F.
        • Englaro P.
        • Hanitsch S.
        • et al.
        Plasma leptin levels in healthy children and adolescents.
        J Clin Endocrinol Metab. 1997; 82: 2904-2910
        • Cizza G.
        • Dorn L.D.
        • Lotsikas A.
        • et al.
        Circulating plasma leptin and IGF-1 levels in girls with premature adrenarche.
        Horm Metab Res. 2001; 33: 138-143
        • Milewich L.
        • Garcia R.L.
        • Gerrity L.W.
        Steroid sulfatase and 17β-hydroxysteroid oxidoreductase activities in mouse tissues.
        J Steroid Biochem. 1984; 21: 529-538
        • Liu C.H.
        • Laughlin G.A.
        • Fischer U.G.
        • et al.
        Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in postmenopausal women.
        J Clin Endocrinol Metab. 1990; 71: 900-906
        • Pavlov E.P.
        • Harman S.M.
        • Chrousos G.P.
        • et al.
        Responses of plasma adrenocorticotropin, cortisol, and dehydroepiandrosterone to ovine corticotropin-releasing hormone in healthy aging men.
        J Clin Endocrinol Metab. 1986; 62: 767-772
        • Rotter J.I.
        • Wong F.L.
        • Lifrak E.T.
        • et al.
        A genetic component to the variation of dehydroepiandrosterone sulfate.
        Metabolism. 1985; 34: 731-736
        • Parker L.N.
        • Levin E.R.
        • Lifrak E.T.
        Evidence for adrenocortical adaptation to severe illness.
        J Clin Endocrinol Metab. 1985; 60: 947-952
        • Zipser R.D.
        • Davenport M.W.
        • Martin K.L.
        • et al.
        Hyperreninemic hypoaldosteronism in the critically ill.
        J Clin Endocrinol Metab. 1981; 53: 867-873
        • Labrie F.
        • Belanger A.
        • Simard J.
        • et al.
        DHEA and peripheral androgen and estrogen formation.
        Ann N Y Acad Sci. 1995; 774: 16-28
        • Grodin J.M.
        • Siiteri P.K.
        • MacDonald P.C.
        Source of estrogen production in postmenopausal women.
        J Clin Endocrinol Metab. 1973; 36: 207-214
        • Beeson P.B.
        Age and sex associations of 40 autoimmune diseases.
        Am J Med. 1994; 96: 457-462
        • Olsen N.J.
        • Kovacs W.J.
        Gonadal steroids and immunity.
        Endocr Rev. 1996; 17: 369-384
        • Lockshin M.D.
        Why women?.
        Lupus. 1997; 6: 625-632
        • Wallace D.J.
        The clinical presentation of systemic lupus erythematosus.
        in: Wallace D.J. Hahn B. Dubois’ Lupus Erythematosus. 5th edition. Williams & Wilkins, Baltimore, MD1997: 627-633
        • Mund A.
        • Simson J.
        • Rothfield N.
        Effect of pregnancy on the course of SLE.
        JAMA. 1963; 183: 917-920
        • Petri M.
        Systemic lupus erythematosus and pregnancy.
        Rheum Dis Clin North Am. 1994; 20: 87-118
        • Urowitz M.B.
        • Gladman D.D.
        • Farewell V.T.
        • et al.
        Lupus and pregnancy studies.
        Arthritis Rheum. 1993; 36: 1392-1397
        • Roubinian J.R.
        • Papoian R.
        • Talal N.
        Androgenic hormones modulate autoantibody responses and improve survival in murine lupus.
        J Clin Invest. 1977; 59: 1066-1070
        • Lucas J.A.
        • Ahmed S.A.
        • Casey M.L.
        • et al.
        Prevention of autoantibody formation and prolonged survival in New Zealand black/New Zealand white F1 mice fed dehydroisoandrosterone.
        J Clin Invest. 1985; 75: 2091-2093
        • Bizzarro A.
        • Valentini G.
        • Di Martino G.
        • et al.
        Influence of testosterone therapy on clinical and immunological features of autoimmune diseases associated with Klinefelter’s syndrome.
        J Clin Endocrinol Metab. 1987; 64: 32-36
        • Olsen N.J.
        • Kovacs W.J.
        Case report.
        Am J Med Sci. 1995; 310: 158-160
        • Wofsy D.
        • Murphy E.D.
        • Roths J.B.
        • et al.
        Deficient interleukin 2 activity in MRL/Mp and C57BL/6J mice bearing the lpr gene.
        J Exp Med. 1981; 154: 1671-1680
        • Daynes R.A.
        • Dudley D.J.
        • Araneo B.A.
        Regulation of murine lymphokine production in vivo. II. Dehydroepiandrosterone is a natural enhancer of interleukin 2 synthesis by helper T cells.
        Eur J Immunol. 1990; 20: 793-802
        • Alcocer-Varela J.
        • Alarcon-Segovia D.
        Decreased production of and response to interleukin-2 by cultured lymphocytes from patients with systemic lupus erythematosus.
        J Clin Invest. 1982; 69: 1388-1392
        • Linker-Israeli M.
        • Bakke A.C.
        • Kitridou R.C.
        • et al.
        Defective production of interleukin 1 and interleukin 2 in patients with systemic lupus erythematosus (SLE).
        J Immunol. 1983; 130: 2651-2655
        • Suzuki T.
        • Suzuki N.
        • Daynes R.A.
        • et al.
        Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells.
        Clin Immunol Immunopathol. 1991; 61: 202-211
        • Lahita R.G.
        • Bradlow H.L.
        • Kunkel H.G.
        • et al.
        Alterations of estrogen metabolism in systemic lupus erythematosus.
        Arthritis Rheum. 1979; 22: 1195-1198
        • Lahita R.G.
        • Bradlow H.L.
        • Kunkel H.G.
        • et al.
        Increased 16 alpha-hydroxylation of estradiol in systemic lupus erythematosus.
        J Clin Endocrinol Metab. 1981; 53: 174-178
        • Lahita R.G.
        • Bradlow H.L.
        • Fishman J.
        • et al.
        Estrogen metabolism in systemic lupus erythematosus.
        Arthritis Rheum. 1982; 25: 843-856
        • Zhu B.T.
        • Conney A.H.
        Review.
        Carcinogenesis. 1998; 19: 1-27
        • Fishman J.
        • Martucci C.
        Biological properties of 16 alpha-hydroxyestrone.
        J Clin Endocrinol Metab. 1980; 51: 611-615
        • Bucala R.
        • Fishman J.
        • Cerami A.
        Formation of covalent adducts between cortisol and 16 alpha-hydroxyestrone and protein.
        Proc Natl Acad Sci. 1982; 79: 3320-3324
        • Lahita R.G.
        • Bradlow H.L.
        Klinefelter’s syndrome.
        J Rheumatol. 1987; 14: 154-157
        • Lamberts S.W.
        • Verleun T.
        • Hofland L.
        • et al.
        Differences in the interaction between dopamine and estradiol on prolactin release by cultured normal and tumorous human pituitary cells.
        J Clin Endocrinol Metab. 1986; 63: 1342-1347
        • Shupnik M.A.
        • Pitt L.K.
        • Soh A.Y.
        • et al.
        Selective expression of estrogen receptor alpha and beta isoforms in human pituitary tumors.
        J Clin Endocrinol Metab. 1998; 83: 3965-3972
        • Fishman J.
        • Tulchinsky D.
        Suppression of prolactin secretion in normal young women by 2-hydroxyestrone.
        Science. 1980; 210: 73-74
        • Sabharwal P.
        • Glaser R.
        • Lafuse W.
        • et al.
        Prolactin synthesized and secreted by human peripheral blood mononuclear cells.
        Proc Natl Acad Sci. 1992; 89: 7713-7716
        • Hiestand P.C.
        • Mekler P.
        • Nordmann R.
        • et al.
        Prolactin as a modulator of lymphocyte responsiveness provides a possible mechanism of action for cyclosporine.
        Proc Natl Acad Sci. 1986; 83: 2599-2603
        • Jara L.J.
        • Lavalle C.
        • Espinoza L.R.
        Does prolactin have a role in the pathogenesis of systemic lupus erythematosus?.
        J Rheumatol. 1992; 1: 1333-1336
        • Chikanza I.C.
        • Petrou P.
        • Kingsley G.
        • et al.
        Defective hypothalamic response to immune and inflammatory stimuli in patients with rheumatoid arthritis.
        Arthritis Rheum. 1992; 35: 1281-1288
        • Chrousos G.P.
        The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation.
        N Engl J Med. 1995; 332: 1351-1362
        • Masi A.T.
        • Chrousos G.P.
        Hypothalamic-pituitary-adrenal-glucocorticoid axis function in rheumatoid arthritis.
        J Rheumatol. 1996; 23: 577-581
        • Cutolo M.
        • Foppiani L.
        • Prete C.
        • et al.
        Hypothalamic-pituitary-adrenocortical axis function in premenopausal women with rheumatoid arthritis not treated with glucocorticoids.
        J Rheumatol. 1999; 26: 282-288
        • Crofford L.J.
        • Kalogeras K.T.
        • Mastorakos G.
        • et al.
        Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones.
        J Clin Endocrinol Metab. 1997; 82: 1279-1283
        • Schlaghecke R.
        • Kornely E.
        • Wollenhaupt J.
        • et al.
        Glucocorticoid receptors in rheumatoid arthritis.
        Arthritis Rheum. 1992; 35: 740-744
        • Masi A.T.
        • Josipovic D.B.
        • Jefferson W.E.
        Low adrenal androgenic-anabolic steroids in women with rheumatoid arthritis (RA).
        Semin Arthritis Rheum. 1984; 14: 1-23
        • Cutolo M.
        • Masi A.T.
        Do androgens influence the pathophysiology of rheumatoid arthritis? Facts and hypotheses.
        J Rheumatol. 1998; 25: 1041-1047
        • Masi A.T.
        • Chrousos G.P.
        • Bornstein S.R.
        Enigmas of adrenal androgen and glucocorticoid dissociation in premenopausal onset rheumatoid arthritis.
        J Rheumatol. 1999; 26: 247-250
        • Ehrhart-Bornstein M.
        • Hinson J.P.
        • Bornstein S.R.
        • et al.
        Intraadrenal interactions in the regulation of adrenocortical steroidogenesis.
        Endocr Rev. 1998; 19: 101-143
        • Nussdorfer G.G.
        • Mazzocchi G.
        Immune-endocrine interactions in the mammalian adrenal gland.
        Int Rev Cytol. 1998; 183: 143-184
        • Reichlin S.
        Neuroendocrine-immune interactions.
        N Engl J Med. 1993; 329: 1246-1253
        • Hennebold J.D.
        • Daynes R.A.
        Regulation of macrophage dehydroepiandrosterone sulfate metabolism by inflammatory cytokines.
        Endocrinology. 1994; 135: 67-75
        • Straub R.H.
        • Konecna L.
        • Hrach S.
        • et al.
        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.
        J Clin Endocrinol Metab. 1998; 83: 2012-2017
        • Kimura M.
        • Tanaka S.
        • Yamada Y.
        • et al.
        Dehydroepiandrosterone decreases serum tumor necrosis factor-alpha and restores insulin sensitivity.
        Endocrinology. 1998; 139: 3249-3253
        • Padgett D.A.
        • Loria R.M.
        Endocrine regulation of murine macrophage function.
        J Neuroimmunol. 1998; 84: 61-68
        • Cutolo M.
        • Accardo S.
        • Villaggio
        • et al.
        Androgen and estrogen receptors are present in primary cultures of human synovial macrophages.
        J Clin Endocrinol Metab. 1996; 81: 8320-8327
        • Vaishnaw A.K.
        • McNally J.D.
        • Elkon K.B.
        Apoptosis in the rheumatic diseases.
        Arthritis Rheum. 1997; 40: 1917-1927
        • Cutolo M.
        • Sulli A.
        • Barone A.
        • et al.
        Sex hormones, proto-oncogene expression and apoptosis.
        Clin Exp Rheumatol. 1996; 14: 87-94
        • Seki M.
        • Ushiyama C.
        • Seta N.
        • et al.
        Apoptosis of lymphocytes induced by glucocorticoids and relationship to therapeutic efficacy in patients with systemic lupus erythematosus.
        Arthritis Rheum. 1998; 41: 823-830
        • Rosen A.
        • Casciola-Rosen L.
        Autoantigens as substrates for apoptotic proteases.
        Cell Death Differ. 1999; 6: 6-12
        • Schwartzman R.A.
        • Cidlowski J.A.
        Apoptosis.
        Endocr Rev. 1993; 14: 133-151
        • Hedman M.
        • Nilsson E.
        • de la Torre B.
        Low blood and synovial fluid levels of sulpho-conjugated steroids in rheumatoid arthritis.
        Clin Exp Rheumatol. 1992; 10: 25-30
        • van Vollenhoven R.F.
        • Engleman E.G.
        • McGuire J.L.
        An open study of dehydroepiandrosterone in systemic lupus erythematosus.
        Arthritis Rheum. 1994; 37: 1305-1310
        • van Vollenhoven R.F.
        • Engleman E.G.
        • McGuire J.L.
        Dehydroepiandrosterone in systemic lupus erythematosus. Results of a double-blind, placebo-controlled, randomized clinical trial.
        Arthritis Rheum. 1995; 38: 1826-1831
        • Petri M.
        • Lahita R.
        • McGuire J.
        • et al.
        Results of the GL701 (DHEA) Multicenter Steroid-Sparing SLE Study.
        Arthritis Rheum. 1997; 40 (abstract): S327