Semin Reprod Med 2004; 22(4): 369-377
DOI: 10.1055/s-2004-861553
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Adrenal Androgens and the Immune System

Chi Chiung Grace Chen1 , C. Richard Parker1  Jr. 
  • 1Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama
Further Information

Publication History

Publication Date:
05 January 2005 (online)

ABSTRACT

Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are the main adrenal androgens (AAs) produced in humans. Production of these steroids, like that of cortisol, is under the control of hypothalamic corticotropin-releasing hormone (CRH) and pituitary ACTH. Other factors, however, appear to be involved in AA secretion because there are many instances in which their circulating levels do not change in parallel to those of cortisol. Apart from physiological alterations associated with fetal adrenal regression, adrenarche and aging, the main instances of divergence in AA production compared with those of corticosteroids occur when immune function is activated or is aberrant. Relative reductions in DHEA and DHEAS have been noted in subjects with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), human immunodeficiency virus (HIV) and autoimmune deficiency syndrome (AIDS), sepsis, and trauma. In some instances, differences in the AA responses have been linked to a clinical course. The mechanisms for impairments in AA production in the absence of suppressed corticoid secretion are unclear but may involve circulating cytokines or locally released mediators from immune system cells in the adrenal gland. There also is evidence that DHEA and DHEAS play a role in immune competence, displaying biological effects opposite to those of corticosteroids.

REFERENCES

  • 1 Longcope C. Metabolism of DHEA.  Ann N Y Acad Sci. 1995;  774 143-148
  • 2 Baulieu E E. Dehydroepiandrosterone (DHEA): a fountain of youth?.  J Clin Endocrinol Metab. 1996;  81 3147-3151
  • 3 Albertson B D, Hobson W C, Burnett B S et al.. Dissociation of cortisol and AA secretion in the hypophysectomized adrenocorticotropin-replaced chimpanzee.  J Clin Endocrinol Metab. 1984;  59 13-18
  • 4 Migeon C J, Keller A R, Lawrence B, Shepard II T H. Dehydroepiandrosterone and androsterone levels in human plasma. Effect of age and sex; day to day variations.  J Clin Endocrinol Metab. 1957;  17 1051-1062
  • 5 Orentreich N, Brind J L, Rizer R L, Vogelman J H. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood.  J Clin Endocrinol Metab. 1984;  59 551-555
  • 6 Labrie F, Belanger A, Cusan L, Gomez J L, Candas B. Major decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging.  J Clin Endocrinol Metab. 1997;  82 2396-2402
  • 7 Genazzani A T, Facchinetti F, Pintor C et al.. Proopiocortin-related peptide plasma levels throughout prepuberty and puberty.  J Clin Endocrinol Metab. 1983;  57 56-61
  • 8 Parker Jr C R, Slayden S M, Azziz R et al.. Effects of aging on adrenal function in the human: responsiveness and sensitivity of adrenal androgens and cortisol to adrenocorticotropin in premenopausal and postmenopausal women.  J Clin Endocrinol Metab. 2000;  85 48-54
  • 9 Vermeulen A, Deslypere J P, Schelfhout W, Verdonck L, Rubens R. Adrenocortical function in old age: response to acute adrenocorticotropin stimulation.  J Clin Endocrinol Metab. 1982;  54 187-191
  • 10 Masi A T, Da Silva J A, Cutolo M. Perturbations of hypothalamic-pituitary-gonadal (HPG) axis and adrenal androgen (AA) functions in rheumatoid arthritis.  Baillieres Clin Rheumatol. 1996;  10 295-332
  • 11 Hedman M, Nilsson E, de la Torre B. Low sulpho-conjugated steroid hormone levels in systemic lupus erythematosus (SLE).  Clin Exp Rheumatol. 1989;  7 583-588
  • 12 Marx C, Bornstein S R, Wolkersdorfer G W et al.. Relevance of major histocompatibility complex class II expression as a hallmark for the cellular differentiation in the human adrenal cortex.  J Clin Endocrinol Metab. 1997;  82 3136-3140
  • 13 Parker Jr C R, Mixon R L, Brissie R L, Grizzle W E. Aging alters zonation in the adrenal cortex of men.  J Clin Endocrinol Metab. 1997;  82 3898-3900
  • 14 Hayashi Y, Hiyoshi T, Takemura T, Kurashima C, Hirokawa K. Focal lymphocyte infiltration in the adrenal cortex of the elderly: immunohistological analysis of infiltrating lymphocytes.  Clin Exp Immunol. 1989;  77 101-105
  • 15 Gonzalez-Hernandez J A, Bornstein S R, Ehrhart-Bornstein M et al.. Macrophages within the human adrenal gland.  Cell Tissue Res. 1994;  278 201-205
  • 16 Chrousos G P. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation.  N Engl J Med. 1995;  332 1351-1362
  • 17 Ehrhart-Bornstein M, Hinson J P, Bornstein S R et al.. Intradrenal interactions in the regulation of adrenocortical steroidogenesis.  Endocr Rev. 1998;  19 101-143
  • 18 Wolkersdorfer G W, Lohmann T, Marx C et al.. Lymphocyte stimulate dehydroepiandrosterone production through direct cellular contact with adrenal zona reticularis cells: a novel mechanism of immune-endocrine interaction.  J Clin Endocrinol Metab. 1999;  84 4220-4227
  • 19 Lebrethon M C, Jaillard C, Naville B, Begeot M, Saez J M. Effects of transforming growth factor β-1 on human adrenocortical fasciculata-reticularis cell differentiated functions.  J Clin Endocrinol Metab. 1994;  79 1033-1039
  • 20 Jettela M, Ilvesmaki V, Voutilainen R et al.. Tumor necrosis factor as a potent inhibitor of adrenocorticotropin-induced cortisol production and steroidogenic P450 enzyme gene expression in cultured human fetal adrenal cells.  Endocrinology. 1991;  128 623-629
  • 21 Stankovic A K, Parker Jr C R. Effects of transforming growth factor-β on human fetal adrenal steroid production.  Mol Cell Endocrinol. 1994;  99 145-151
  • 22 Parker Jr C R, Stankovic A K, Falany C N, Grizzle W E. Effect of TGF-β on dehydroepiandrosterone sulfotransferase in cultured human fetal adrenal cells.  Ann NY Acad Sci. 1995;  774 326-328
  • 23 de la Torre B, Hedman M, Nilsson E et al.. Relationship between blood and joint tissue DHEAS levels in rheumatoid arthritis and osteoarthritis.  Clin Exp Rheumatol. 1993;  11 597-601
  • 24 Leithauser F, Dhein J, Mechtersheimer G et al.. Constitutive and induced expression of APO-1, a new member of the nerve growth factor/tumor necrosis factor receptor superfamily, in normal and neoplastic cells.  Lab Invest. 1993;  69 415-429
  • 25 Itoh N, Yonehara S, Ishii A et al.. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis.  Cell. 1991;  66 233-243
  • 26 Viard I, Hall S H, Jaillard C et al.. Regulation of c-fos, c-jun and jun-B messenger ribonucleic acids by angiotensin-II and corticotropin in ovine and bovine adrenocortical cells.  Endocrinology. 1992;  130 1193-1200
  • 27 Marx C, Wolkersdorfer G W, Bornstein S R. A new view on immune-adrenal interactions: role for Fas and Fas ligand?.  Neuroimmunomodulation. 1998;  5 5-8
  • 28 Besedovsky H O, Del Rey A. Immune-neuro-endocrine interactions.  Endocr Rev. 1996;  17 64-102
  • 29 Cutolo M, Foppiani L, Prete C et al.. Hypothalamic-pituitary-adrenocortical axis in premenopausal rheumatoid arthritis patients not treated with glucocorticoids.  J Rheumatol. 1999;  26 282-288
  • 30 Path G, Bornstein S R, Ehrhart-Bornstein M, Scherbaum W A. Interleukin-6 and the interleukin-6 receptor in the human adrenal gland: expression and effects on steroidogenesis.  J Clin Endocrinol Metab. 1997;  82 2343-2349
  • 31 Bornstein S R, Ehrhart-Bornstein M, Guse-Behling H, Scherbaum W A. Structure and dynamics of adrenal mitochondria following stimulation with corticotropin releasing hormone (CRH).  Anat Rec. 1992;  234 255-262
  • 32 Straub R H, Gluck T, Cutolo M et al.. The adrenal steroid status in relation to inflammatory cytokines (IL-6 and TNF) in polymyalgia rheumatica.  Rheumatology. 2000;  39 624-631
  • 33 Gudbjornsson B, Skogseid B, Oberg B et al.. Intact adrenocorticotropic hormone secretion but impaired cortisol response in patients with active rheumatoid arthritis. Effect of glucocorticoids.  J Rheumatol. 1996;  23 596-602
  • 34 Masi A T, Chrousos G P. Hypothalamic-pituitary-adrenal-glucocorticoid axis function in rheumatoid arthritis.  J Rheumatol. 1996;  23 577-581
  • 35 Parker L N, Levin E R, Lifrak E T. Evidence for adrenocortical adaptation to severe illness.  J Clin Endocrinol Metab. 1985;  60 947-952
  • 36 Straub R H, Miller L E, Scholmerich J, Zietz B. Cytokines and hormones as possible links between endocrinosenescence and immunosenescence.  J Neuroimmunol. 2000;  109 10-15
  • 37 Miller W L, Auchus R J, Geller D H. The regulation of 17,20 lyase activity.  Steroids. 1997;  62 133-142
  • 38 Hales D B. Interleukin-1 inhibits Leydig cell steroidogenesis primarily by decreasing 17 alpha-hydroxylase/C17-20 lyase cytochrome P450 expression.  Endocrinology. 1992;  131 2165-2172
  • 39 Kalimi M, Shafagoj Y, Loria R M et al.. Anti-glucocorticoid effect of dehydroepiandrosterone (DHEA).  Mol Cell Biochem. 1994;  131 99-104
  • 40 Maurer M, Trajanoski Z, Frey G et al.. Differential gene expression profile of glucocorticoids, testosterone and dehydroepiandrosterone in human cells.  Horm Metab Ress. 2001;  33 691-695
  • 41 Regelson W, Kalimi M. Dehydroepiandrosterone (DHEA)-the multifunctional steroid II. Effects on the CNS, cell proliferation, metabolic and vascular, clinical and other effects. Mechanism of action?.  Ann N Y Acad Sci. 1994;  719 564-575
  • 42 May M, Holmes E, Rogers W, Poth M. Protection from glucocorticoid induced thymic involution by dehydroepiandrosterone.  Life Sci. 1990;  46 1627-1631
  • 43 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
  • 44 McLachlan J A, Serkin C D, Barouche O. Dehydroepiandrosterone modulation of lipopolysaccharide-stimulated monocyte cytotoxicity.  J Immunol. 1996;  156 328-335
  • 45 Clerici M, Shearer G M. The Th1-Th2 hypothesis of HIV infection: New insights.  Immunol Today. 1994;  15 575-581
  • 46 Jacobson M A, Fusaro R E, Galmarini M, Lang W. Decreased serum dehydroepiandrosterone is associated with an increased progression of human immunodeficiency virus infection in men with CD4 cells counts of 200-499.  J Infect Dis. 1991;  164 864-868
  • 47 van Griensven M, Dahlweid F M, Giannoudis P V et al.. Dehydroepiandrosterone (DHEA) modulates the activity and expression of lymphocyte subpopulations induced by cecal ligation and puncture.  Shock. 2002;  18 445-449
  • 48 Oberbeck R, Dahlweid M, Koch R et al.. Dehydroepiandrosterone decreases mortality rate and improves cellular immune function during polymicrobial sepsis.  Crit Care Med. 2001;  29 380-384
  • 49 Casson P R, Andersen R N, Herrod H G et al.. Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women.  Am J Obstet Gynecol. 1993;  169 1536-1539
  • 50 Frenkel R A, Slaughter C A, Orth K et al.. Peroxisome proliferation and induction of peroxisomal enzymes in mouse and rat liver by dehydroepiandrosterone feeding.  J Steroid Biochem. 1990;  35 333-342
  • 51 Poynter M E, Daynes R A. Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging.  J Biol Chem. 1998;  273 32833-32841
  • 52 Dashtaki R, Whorton A R, Murphy T M et al.. Dehydroepiandrosterone and analogs inhibit DNA binding of AP-1 and airway smooth muscle proliferation.  J Pharmacol Exp Ther. 1998;  285 876-883
  • 53 Araghi-Niknam M, Zhang Z, Jiang S et al.. Cytokine dysregulation and increased oxidation is prevented by dehydroepiandrosterone in mice infected with murine leukemia retrovirus.  Proc Soc Exp Biol Med. 1997;  216 386-391
  • 54 Danenberg H D, Alpert G, Lustig S, Ben-Nathan D. Dehydroepiandrosterone protects mice from endotoxin toxicity and reduces tumor necrosis factor production.  Antimicrob Agents Chemother. 1992;  36 2275-2279
  • 55 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: possible link between endocrinosenescence and immunosenescence.  J Clin Endocrinol Metab. 1998;  83 2012-2017
  • 56 Spencer N F, Norton S D, Harrison L L et al.. Dysregulation of IL-10 production with aging: possible linkage to the age-associated decline in DHEA and its sulfated derivatives.  Exp Gerontol. 1996;  31 393-408
  • 57 Kanda N, Tsuchida T, Tanaki K. Testosterone suppresses anti-DNA antibody production in peripheral blood mononuclear cells from patients with systemic lupus erthematosus.  Arthritis Rheum. 1997;  40 1703-1711
  • 58 Deshpande R, Khalili H, Pergolizzi R G et al.. Estradiol down-regulates LPS-induced cytokine production and NF-κB activation in murine macrophages.  Am J Reprod Immunol. 1997;  38 46-54
  • 59 Pung O J, Tucker A N, Vore S J, Luster M I. Influence of estrogen on host resistance: increased susceptibility of mice to Listeria monocytogenes correlates with depressed production of interleukin 2.  Infect Immun. 1985;  50 91-96
  • 60 Wilder R L. Neuroendocrine-immune system interactions and autoimmunity.  Annu Rev Immunol. 1995;  13 307-333
  • 61 Wilder R L. Adrenal and gonadal steroid hormone deficiency in the etiopathogenesis of rheumatoid arthritis.  J Rheumatol. 1996;  23 10-12
  • 62 Barrett J H, Brennan P, Fiddler M, Silman A J. Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy.  Arthritis Rheum. 1999;  42 1219-1227
  • 63 Cutolo M, Castagnetta L. Immunomodulatory mechanisms mediated by sex hormones in rheumatoid arthritis.  Ann N Y Acad Sci. 1996;  784 237-251
  • 64 McKenna T J, Fearon U, Clarke D, Cunningham S K. A critical review of the origin and control of Adrenal Androgens.  Baillieres Clin Obstet Gynaecol. 1997;  11 229-248
  • 65 Huang J, Ushiyama K, Mori K, Hukuda S. Possible association of CYP17 gene polymorphism with the onset of rheumatoid arthritis.  Clin Exp Rheumatol. 1999;  17 721-724
  • 66 Cutolo M, Villaggio B, Sulli A et al.. CYP 17 polymorphism and androgen levels in post-menopausal patients with rheumatoid arthritis.  Clin Exp Rheumatol. 2000;  18 420-421
  • 67 Buller K M, Xu Y, Day T A. Indomethacin attenuates oxytocin and hypothalamic-pituitary-adrenal axis responses to systemic interleukin-1 beta.  J Neuroendocrinol. 1998;  10 519-528
  • 68 Petri M, Howard D, Repke J. Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience.  Arthritis Rheum. 1991;  34 1538-1545
  • 69 Jungers P, Kuttenn F, Liote F et al.. Hormonal modulation in systemic lupus erythematosus: preliminary clinical and hormonal results with cyproterone acetate.  Arthritis Rheum. 1985;  28 1243-1250
  • 70 Jungers P, Nahoul K, Pellisier C et al.. Low plasma androgens in women with active or quiescent systemic lupus erythematosus.  Arthritis Rheum. 1982;  25 454-457
  • 71 Lahita R G, Kunkel H G, Bradlow H L. Increased oxidation of testosterone in systemic lupus erythematosus.  Arthritis Rheum. 1983;  26 1517-1521
  • 72 Lahita R G, Bradlow H L, Ginzler E et al.. Low plasma androgens in women with systemic lupus erythematosus.  Arthritis Rheum. 1987;  30 241-248
  • 73 Suzuki N, Suzuki T, Sakane T. hormones and lupus: Defective dehydroepiandrosterone activity induces impaired interleukin-2 activity of T lymphocytes in patients with systemic lupus erythematosus.  Ann Med Interne. 1996;  147 248-252
  • 74 Straub R H, Zeuner M, Antoniou E et al.. Dehydroepiandrosterone sulfate is positively correlated with soluble interleukin 2 receptor and soluble intercellular adhesion molecule in systemic lupus erythematosus.  J Rheumatol. 1996;  23 856-861
  • 75 Alcocer-Varela J, Alarcon-Segovia D. Decreased production of and response of interleukin-2 by cultured lymphocytes from patients with systemic lupus erythematosus.  J Clin Invest. 1982;  69 1388-1392
  • 76 van Vollenhoven R F, McDevitt H O. Studies of the treatment of nephritis in NZB/NZW mice with dehydroepiandrosterone.  Arthritis Rheum. 1992;  35 S207
  • 77 van Vollenhoven R F, Morabito L M, Engleman E G, McGuire J L. Treatment of systemic lupus erthematosus with dehydroepiandrosterone: 50 patients treated up to 12 months.  J Rheumatol. 1998;  25 2352-2356
  • 78 Petri M, Lahita R, van Vollenhoven R F et al.. Effects of prasterone on corticosteroid requirements of women with systemic lupus erythermtosis.  Arthritis Rheum. 2002;  46 1820-1829
  • 79 Giltay E J, van Schrdenburg D, Gooren L J, Dijkmans B A. Dehydroepiandrosterone sulfate in patients with rheumatoid arthritis.  Ann N Y Acad Sci. 1999;  876 152-154
  • 80 Carr D J. Increased levels of IFN-gamma in the trigeminal ganglion correlate with protection against HSV-1 induced encephalitis following subcutaneous administration with androstenediol.  J Neuroimmunol. 1998;  89 160-167
  • 81 Gougeon M L, Debatin K M. Molecular control of programmed cell death in HIV infection: contribution to the dysregulation of T cell homeostasis and to CD4 T cell depletion. In: Dalgleish AG, Weiss RA HIV and the New Viruses, 2nd ed. New York; Academic Press 1999: 99-114
  • 82 Grunfeld C, Kotler D P. Pathology of AIDS wasting syndrome. In: Volberding P, Jacobson MA AIDS Clinical Review. New York; Dekker 1992: 191-199
  • 83 Lortholary O, Christeff N, Casassus P et al.. Hypothalamo-pituitary-adrenal function in HIV infected men.  J Clin Endocrinol Metab. 1996;  81 791-796
  • 84 Sellmeyer D E, Grunfeld C. Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome.  Endocr Rev. 1996;  17 518-532
  • 85 de la Torre B, von Krogh G, Svensson M, Holmberg V. Blood cortisol and dehydroepiandrosterone sulfate (DHEAS) levels and CD4 T cell counts in HIV infection.  Clin Exp Rheumatol. 1997;  15 87-90
  • 86 Christeff N, Nunez E A, Gougeon M L. Changes in cortisol-DHEA ratio in HIV-infected men are related to immunological and metabolic perturbations leading to malnutrition and lipodystrophy.  Ann N Y Acad Sci. 2000;  917 962-970
  • 87 Piedrola G, Casado J L, Lopez E et al.. Clinical features of adrenal insufficiency in patients with acquired immunodeficiency syndrome.  Clin Endocrinol. 1996;  45 97-101
  • 88 Schein R MH, Sprung C L, Marcial E et al.. Plasma cortisol levels in patients with septic shock.  Crit Care Med. 1990;  18 259-263
  • 89 Lephart E D, Baxter C R, Parker Jr C R. Effect of burn trauma on adrenal and testicular steroid production.  J Clin Endocrinol Metab. 1987;  64 842-848
  • 90 Marx C, Petros S, Bornstein S R et al.. Adrenocortical hormones in survivors and nonsurvivors of severe sepsis: Diverse time course of dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and cortisol.  Crit Care Med. 2003;  31 1382-1388
  • 91 Bornstein S R, Wolkersdorfer G W, Tauchnitz R et al.. Plasma dehydroepiandrosterone levels during experimental endotoxemia and anti-inflammatory therapy in humans.  Crit Care Med. 2000;  28 2103-2106
  • 92 Schuld A, Mullington J, Friess E et al.. Changes in dehydroepiandrosterone (DHEA) and DHEA-sulfate plasma levels during experimental endotoxemia in healthy volunteers.  J Clin Endocrinol Metab. 2000;  85 4624-4629

C. Richard Parker JrPh.D. 

Department of Obstetrics and Gynecology, University of Alabama at Birmingham

618 South 20th Street, 360 Old Hillman Building

Birmingham, AL 35294-7333

Email: crparker@uab.edu