sign in sign up
<<
Home , Androstenediol

JOURNAL OF ADOLESCENT HEALTH 2002;30S:37–43

SUPPLEMENT ARTICLE

Autoimmunity, (DHEA), and Stress

KENNETH E. SCHWARTZ, M.D.

KEY WORDS: Autoimmunity DHEA Stress Androgenic Systemic lupus erythematosus Rheumatoid arthritis

Steroids secreted by the adult have which control the synthesis and release of adrenal been generally classified as , glu- remain unclear. cocorticoids, and androgenic steroids. Although the The principal adrenal is dehydroepi- diverse effects of on the immune (DHEA), which is secreted primarily in system are well-recognized, attention is beginning to its sulfated form, DHEA-S. DHEA secretion is mini- focus on the potential role of androgenic steroids as mal in childhood until the onset of adrenarche, which immunomodulators. This paper will primarily focus generally occurs between 6 and 8 years of age [1]. At on some of the recent advances in our understanding this time, serum concentrations of adrenal steroids of interactions between adrenal androgenic steroids (DHEA, DHEA-S, and ) begin to rise and the . while production and excretion of remain con- stant and gonadotropin levels are still prepubertal [2]. Adrenal Androgen Synthesis and Secretion Various mechanisms have been proposed for the initiation of adrenarche, which is characterized by a Pregenenolone, derived by side chain cleavage (SCC) dissociation of secretion of adrenal androgens from of , is metabolized by various steroido- that of glucocorticoids and mineralocorticoids. Al- genic enzymes along the , glu- though hypothalamic/pituitary peptides may be in- cocorticoid, and androgenic pathways which corre- volved [2], recent data suggest there is an age-related spond to the three functional zones of the adrenal: decreased expression of 3␤- hydroge- the glomerulosa, fasciculata, and the fasciculata/ nase (3␤-HSD) in human adrenal reticularis, suggest- reticularis (Figure 1). Although secretion of aldoste- ing there may be preferential diversion of rone in the zona glomerulosa is largely regulated by precursors along androgenic pathways shortly be- the renin-angiotensin system and cortisol by the fore onset of adrenarche [3]. CRH-ACTH system, the physiologic mechanisms A single protein, cytochrome P450c17, catalyzes both the conversion of to 17-OH preg- From Genelabs Technologies, Inc., Redwood City, California. nenolone (17␣-hydroxylase enzymatic step) and the Address correspondence to: Kenneth E. Schwartz, M.D., Genelabs conversion of 17-OH pregnenolone to DHEA (17,20 Technologies, Inc., 505 Penobscot Drive, Redwood City, CA 94063. E-mail: [email protected]. lyase enzymatic step) [4]. Serine phosphorylation of Manuscript accepted September 14, 2001. cytochrome P450c17 to catalyze 17,20 lyase activity

© Society for Adolescent Medicine, 2002 1054-139X/02/$–see front matter Published by Elsevier Science Inc., 655 Avenue of the Americas, New York, NY 10010 PII S1054-139X(01)00385-8 38 SCHWARTZ JOURNAL OF ADOLESCENT HEALTH Vol. 30, No. 4S

Figure 1. Adrenal Cortex Biosynthetic Pathways. Steroidogenic enzymes are as follows: CYP11A1 (side chain cleavage enzyme); 3␤-HSD (3␤-hydroxysteroid dehydrogenase); CYP17 (17␣ hydroxylase/17,20 lyase); CYP21A2 (21-hydroxylase); CYP11B1 (11␤-hydroxylase) and CYP11B2 ( synthase).

has been reported as a potential mechanism for lowing burns or acute trauma, and psychological differential regulation of these two steps [5,6]. Lep- stress as encountered prior to surgery. Decreased tin, the adipostatic hormone synthesized and se- DHEA and DHEA-S blood levels and diminished creted by fat tissues, directly correlates with body ACTH-stimulated DHEA reserve occur during acute mass index and percent body fat during childhood, stress while basal and ACTH-stimulated cortisol and may be a signal for onset of the earliest stages of concentrations are increased, indicating a defect in puberty [7,8]. Girls with premature adrenarche have ACTH-stimulated DHEA reserve during acute ill- elevated blood leptin levels compared to those with ness [14]. This change parallels that of hyperrenine- normal age onset adrenarche [9], and this hormone mic hypoaldosteronism, which also occurs in the may possibly play a permissive role in the initiation seriously ill [15], suggesting a relative shift in the of adrenarche. metabolism of adrenal pregnenolone in serious ill- DHEA is primarily secreted from the adrenal ness away from mineralocorticoids and adrenal an- gland as its sulfated form, DHEA-S, which is the drogens and toward glucocorticoids. This shift of most abundant steroid secreted by the human adre- relative biochemical pathway predominance may be nal gland and which circulates in up to 30-fold a factor necessary for survival during chronic severe concentration greater than cortisol. DHEA-S under- stress. goes conversion to DHEA by steroid sulfatases in Under normal circumstances, DHEA is converted many peripheral tissues [10]. to more potent androgens including androstenedi- DHEA is cosecreted with cortisol in response to ␤ corticotropin-releasing hormone (CRH) and cortico- one and as well as , 17 -estra- ␤ tropin (adrenal corticotropic hormone [ACTH]), and diol and , by the enzymes 3 -hydroxysteroid ␤ ␤ like cortisol, undergoes a diurnal variation with peak dehydrogenase (3 -HSD) and 17 -hydroxysteroid ␤ daily levels occurring in the early morning waking dehydrogenase (17 -HSD) which are found not only hours. Both diurnal variation of DHEA and ACTH- in classic steroidogenic tissues (placenta, adrenal stimulated responsiveness of DHEA release diminish cortex, ovary, and testis) but also in a number of with age [11,12]. DHEA-S does not undergo diurnal peripheral tissues [16]. Its conversion to andro- variation, however, and levels remain relatively sta- stenedione and subsequent aromatization to estra- ble in short-term longitudinal assessments [13]. diol and estrone is thought to account for the major- Dissociation of DHEA from cortisol release is ity of in postmenopausal present during acute stress, such as may occur fol- women [17] (Figure 2). April 2002 AUTOIMMUNITY, DHEA, AND STRESS 39

Figure 2. Interconversion From DHEA to Other Androgenic and Estrogenic Steroids. 3␤-HSD (3␤-hydroxysteroid dehydrogenase); 17␤-HSD (17␤-hydroxysteroid dehydrogenase).

Abnormalities of the Hypothalamic-Pituitary- ance of anti-DNA antibodies, onset of nephritis and Adrenal Axis, Steroid Metabolism, and decrease in mortality in female New Zealand (NZ) Autoimmune Disease B/W F1 hybrid mice, a well-characterized animal The observation that some autoimmune diseases are model for SLE [25,26]. Decreased secretion of inter- more common in females [18] has long raised the leukin-2 occurs in the murine model of SLE and in question as to the role of sex hormones in autoim- SLE patients [29–32]; DHEA has been reported to munity [19,20]. Although not all autoimmune dis- increase secretion of IL-2 by stimulated murine and eases show female predominance [20], there is a human T cells [30,33]. body of evidence that suggests that, at least for Abnormal metabolism of sex steroids including systemic lupus erythematosus (SLE) and rheumatoid decreased levels of androgens (DHEA, DHEA-S, arthritis, abnormalities of metabolism androstenedione, and testosterone) and increased and/or secretion superimposed on a estrogenic activity have been reported in women genetic predisposition may modulate disease activ- with this disease [34–36]. ity. is converted to estrone, a weaker estro- gen, via the type II 17␤-hydroxysteroid dehydroge- nase (17␤-HSD) isozyme [16]. Two major metabolites Systemic Lupus Erythematosus of estrone are 16␣-hydroxy estrone and 2-hydroxy Systemic lupus erythematosus (SLE) afflicts females estrone [37]. 2-hydroxy estrone binds to the classical to males in a 9:1 ratio [21]. Interest in the role of sex , but with a markedly reduced hormones in this disease has stemmed from multiple binding affinity and weaker hormonal potency as lines of evidence, including its peak incidence in compared to estradiol [37,38]. In contrast, 16␣-hy- women of reproductive age, possible pregnancy- droxy estrone retains potent hormonal activity by related flare [22–24], and the amelioration of murine activating the classical estrogen receptor, and exhib- lupus with administration of androgens [25,26]. its minimal affinity for the human sex hormone Klinefelter syndrome is associated with an increased binding globulin [38]. 16␣-hydroxy estrone has also incidence of autoimmune disorders including SLE, been reported to undergo covalent binding to amino rheumatoid arthritis, and Sjogren syndrome; immu- acids and nucleotides, including the estrogen recep- nologic abnormalities and SLE disease activity in tor [38,39], and it is possible that covalent modifica- men with Klinefelter syndrome have been reported tion of proteins may alter self-recognition and per- to improve with testosterone replacement [27,28]. haps be a causative in the link between SLE and Androgen treatment induces delay in the appear- estrogenic hormones [39]. 40 SCHWARTZ JOURNAL OF ADOLESCENT HEALTH Vol. 30, No. 4S

Increased 16-␣ hydroxylation of estrone, as evi- observed prior to onset of RA. Masi et al. observed denced by increased blood levels of 16␣-hy- significantly lower serum DHEA-S levels 3 to 20 droxyestrone and its metabolite, , have been (mean ϭ 12.0) years before the onset of RA in reported in women with SLE [34–36], and interest- premenopausal pre-cases versus matched controls ingly, also in nonaffected first degree relatives of SLE [55]. The abnormalities contributing to low DHEA-S patients [36], suggesting that genetic factors are concentrations in this disease are poorly understood, contributory to enhancement of this metabolic path- but might be related to defects in the HPA axis or way. Increased 16-hydroxylation of estrone has also direct suppression of adrenal androgen secretion by been reported for men with Klinefelter syndrome inflammatory cytokines [56,57]. Whether the low and SLE [40]. blood androgen levels observed in RA is a cause or Prolactin secretion is increased by estradiol and an effect is presently unknown [54,55]. 16␣-hydroxyestrone [41,42] and decreased by 2-hy- droxyestrone [43]. Prolactin is known to stimulate the immune response [44,45] and hyperprolactine- Cytokines and Adrenal Androgens mia has been reported in some patients with SLE [46]. Complex interactions exist between cytokines and adrenal androgens which may serve to regulate inflammation. Tumor necrosis factor-alpha (TNF-␣), Rheumatoid Arthritis interleukin-1 (IL-1) and interleukin-6 (IL-6) play im- portant roles in inflammatory and wound-healing Rheumatoid arthritis (RA) is characterized by abnor- processes. All three are released at inflammatory malities of the hypothalamic-pituitary-adrenal sites and are potent activators of the hypothalamic- (HPA) axis including blunting of the hypothalamic- pituitary-adrenal axis, through which they presum- pituitary-adrenal axis relative to the level of inflam- ably restrain inflammation [48,58]. matory stress [47–51]. Chikanza et al. reported inap- Cytokines IL-1, IL-2, Il-6, and TNF-␣ produced propriately normal plasma ACTH and cortisol levels locally within the adrenal by parencymal cells and for degree of inflammatory stress, normal ACTH macrophages may suppress adrenal androgen pro- release in response to infusion of CRH, and low or duction [56,57]. Furthermore, tissue conversion of low normal circadian cortisol concentrations and DHEA-S to DHEA by macrophages is decreased by blunted cortisol responses to surgery [47]. As blood inflammatory cytokines [59]. Reciprocally, DHEA concentrations of inflammatory cytokines such as can reduce release of inflammatory cytokines IL-1, IL-1, IL-5, IL-6, and tumor necrosis factor ␣ (TNF-␣) IL-6, and TNF-␣ [60–62], and metabolites of DHEA, are often elevated in RA and are activators to the including and androstenetriol may HPA axis, the paradoxical blunting of the HPA also regulate macrophage cytokine secretion [62]. response could suggest a defect in hypothalamic Androgens and estrogen receptors have been re- regulation [47,48], but it is also possible that elevated ported on human synovial macrophages, suggesting cytokines might decrease adrenal glucocorticoid pro- that both androgens and estrogens may act directly duction [49]. Others have reported decreased glu- on human macrophages through receptor-mediated cocorticoid receptors in rheumatoid arthritis patients mechanisms [63]. Although work in this area is still [52], suggesting an additional mechanism for impair- evolving, it appears complex autocrine or paracrine ment of the HPA axis in these patients. interactions between cytokines and adrenal andro- Low blood androgen levels have also been reported gens may exist to control inflammation. in this disease [50, 53–55]. Cutolo et al. [50] evaluated hypothalamic-pituitary-adrenocortical axis function in patients with rheumatoid arthritis who were not previously treated with glucocorticoids in compari- Apoptosis and Androgens son to healthy controls. DHEA and DHEA-S concen- In some systemic autoimmune disorders, lympho- trations were significantly lower in premenopausal cytic apoptosis is defective and may lead to a loss of patients with RA than controls both in the basal state tolerance by inappropriate survival of autoreactive and after ACTH and/or ovine corticotropin releas- cells [64]. Defective apopotosis has been reported in ing hormone whereas significantly higher levels of rheumatoid arthritis, SLE, and other autoimmune interleukin-6 and interleukin-12 levels were found in diseases [65–67]. As steroids are potent mediators of the patients with RA compared to the controls. apoptosis [68], it is conceivable that altered andro- Interestingly, low blood androgens have been genic/estrogenic steroid ratios could participate in April 2002 AUTOIMMUNITY, DHEA, AND STRESS 41

modulation of apoptosis in selected tissues. It has 4. Nakajin S, Shively JE, Yuan PM, et al. Microsomal cytochrome P-450 from neonatal pig testis: Two enzymatic activities (17 been suggested that low blood and synovial fluid alpha-hydroxylase and c17,20-lyase) associated with one pro- levels of sulfated androgens observed in rheumatoid tein. Biochemistry 1981;20:4037–42. arthritis patients may contribute to synovial prolifer- 5. Geller DH, Auchus RJ, Mendonca BB, et al. The genetic and ation in this disease [65,69]. functional basis of isolated 17,20-lyase deficiency. Nat Genet 1997;17:201–5. 6. Miller WL. Early steps in androgen biosynthesis: From cho- lesterol to DHEA. Bailliere’s Clin Endocrinol Metab 1998;12: Therapeutic Trials of DHEA for SLE 67–81. Studies are ongoing to determine whether DHEA 7. Garcia-Mayor RV, Andrade MA, Rios M, et al. Serum leptin levels in normal children: Relationship to age, gender, body can be of therapeutic benefit for SLE [70–72]. Van mass index, pituitary-gonadal hormones, and pubertal state. Vollenhoven et al. [71] treated 28 female patients J Clin Endocrinol Metab 1997;82:2849–55. with DHEA 200 mg/day or placebo for 3 months. 8. Blum WF, Englaro P, Hanitsch S, et al. Plasma leptin levels in Outcomes included the SLE Disease Activity Index healthy children and adolescents: Dependence on body mass index, body fat mass, gender, pubertal state, and testosterone. (SLEDAI) score, patient’s and physician’s overall J Clin Endocrinol Metab 1997;82:2904–10. assessments of disease activity, and concurrent cor- 9. Cizza G, Dorn LD, Lotsikas A, et al. Circulating plasma leptin ticosteroid dosages (which were adjusted as clini- and IGF-1 levels in girls with premature adrenarche: Potential cally indicated). In the patients who were receiving implications of a preliminary study. Horm Metab Res 2001;33: DHEA, the SLEDAI score, patient’s and physician’s 138–43. 10. Milewich L, Garcia RL, Gerrity LW. Steroid sulfatase and overall assessment of disease activity, and concur- 17␤-hydroxysteroid oxidoreductase activities in mouse tis- rent prednisone dosage decreased, whereas in the sues. J Steroid Biochem 1984;21:529–38. patients taking placebo, small increases were seen. 11. Liu CH, Laughlin GA, Fischer UG, et al. Marked attenuation The difference in patient’s assessment between the of ultradian and circadian rhythms of dehydroepiandros- ϭ terone in postmenopausal women: Evidence for a reduced groups was statistically significant (p .022, adjust- 17,20-desmolase enzymatic activity. J Clin Endocrinol Metab ed). Lupus flares occurred more frequently in the 1990;71:900–6. placebo group (p ϭ .053) [71]. 12. Pavlov EP, Harman SM, Chrousos GP, et al. Responses of plasma adrenocorticotropin, cortisol, and dehydroepiandros- terone to ovine corticotropin-releasing hormone in healthy Conclusions aging men. J Clin Endocrinol Metab 1986;62:767–72. 13. Rotter JI, Wong FL, Lifrak ET, et al. A genetic component to Complex hormonal abnormalities which may be the variation of dehydroepiandrosterone sulfate. Metabolism affecting immunologic regulatory pathways are 1985;34:731–6. 14. Parker LN, Levin ER, Lifrak ET. Evidence for adrenocortical present in systemic lupus erythematosus and rheu- adaptation to severe illness. J Clin Endocrinol Metab 1985;60: matoid arthritis. A body of evidence indicates that 947–52. DHEA may function as an immunomodulator, and 15. Zipser RD, Davenport MW, Martin KL, et al. Hyperreninemic abnormal androgen or estrogen metabolism may hypoaldosteronism in the critically ill: A new entity. J Clin possibly be contributory to the pathogenesis of some Endocrinol Metab 1981;53:867–73. 16. Labrie F, Belanger A, Simard J, et al. DHEA and peripheral immunologic diseases. Work is ongoing to determine androgen and estrogen formation: Intracinology. Ann N Y whether treatment with DHEA will provide thera- Acad Sci 1995;774:16–28. peutic utility in systemic lupus erythematosus. 17. Grodin JM, Siiteri PK, MacDonald PC. Source of estrogen production in postmenopausal women. J Clin Endocrinol Dr. Schwartz is an employee of Genelabs Technologies, Inc. which Metab 1973;36:207–14. is sponsoring clinical trials on the use of oral (DHEA) 18. Beeson PB. Age and sex associations of 40 autoimmune for treatment of systemic lupus erythematosus. diseases. Am J Med 1994;96:457–62. 19. Olsen NJ, Kovacs WJ. Gonadal steroids and immunity. Endocr Rev 1996;17:369–84. References 20. Lockshin MD. Why women? Lupus 1997;6:625–32. 1. De Peretti E, Forest MG. Unconjugated dehydroepiandros- 21. Wallace DJ. The clinical presentation of systemic lupus ery- terone plasma levels in normal subjects from birth to adoles- thematosus. In: Wallace DJ, Hahn B (eds). Dubois’ Lupus cence in human: The use of a sensitive radioimmunoassay. Erythematosus, 5th edition. Baltimore, MD: Williams & J Clin Endocrinol Metab 1976;43:982–91. Wilkins, 1997:627–33. 2. Parker LN. Control of adrenal androgen secretion. Endocrinol 22. Mund A, Simson J, Rothfield N. Effect of pregnancy on the Metab Clin North Am 1991;20:401–21. course of SLE. JAMA 1963;183;917–20. 3. Gell JS, Carr BR, Sasano H, et al. Adrenarche results from 23. Petri M. Systemic lupus erythematosus and pregnancy. development of a 3beta-hydroxysteroid dehydrogenase-defi- Rheum Dis Clin North Am 1994;20:87–118. cient adrenal reticularis. J Clin Endocrinol Metab 1998;83: 24. Urowitz MB, Gladman DD, Farewell VT, et al. Lupus and 3695–701. pregnancy studies. Arthritis Rheum 1993;36:1392–7. 42 SCHWARTZ JOURNAL OF ADOLESCENT HEALTH Vol. 30, No. 4S

25. Roubinian JR, Papoian R, Talal N. Androgenic hormones 44. Sabharwal P, Glaser R, Lafuse W, et al. Prolactin synthesized modulate autoantibody responses and improve survival in and secreted by human peripheral blood mononuclear cells: murine lupus. J Clin Invest 1977;59:1066–70. An autocrine growth factor for lymphoproliferation. Proc Natl 26. Lucas JA, Ahmed SA, Casey ML, et al. Prevention of autoan- Acad Sci 1992;89:7713–6. tibody formation and prolonged survival in New Zealand 45. Hiestand PC, Mekler P, Nordmann R, et al. Prolactin as a black/New Zealand white F1 mice fed dehydroisoandros- modulator of lymphocyte responsiveness provides a possible terone. J Clin Invest 1985;75:2091–3. mechanism of action for cyclosporine. Proc Natl Acad Sci 27. Bizzarro A, Valentini G, Di Martino G, et al. Influence of 1986;83:2599–603. testosterone therapy on clinical and immunological features of 46. Jara LJ, Lavalle C, Espinoza LR. Does prolactin have a role in autoimmune diseases associated with Klinefelter’s syndrome. the pathogenesis of systemic lupus erythematosus? J Rheuma- J Clin Endocrinol Metab 1987;64:32–6. tol 1992;1:1333–6. 28. Olsen NJ, Kovacs WJ. Case report: Testosterone treatment of 47. Chikanza IC, Petrou P, Kingsley G, et al. Defective hypotha- systemic lupus erythematosus in a patient with Klinefelter’s lamic response to immune and inflammatory stimuli in pa- syndrome. Am J Med Sci 1995;310:158–60. tients with rheumatoid arthritis. Arthritis Rheum 1992;35: 29. Wofsy D, Murphy ED, Roths JB, et al. Deficient interleukin 2 1281–8. activity in MRL/Mp and C57BL/6J mice bearing the lpr gene. 48. Chrousos GP. The hypothalamic-pituitary-adrenal axis and J Exp Med 1981;154:1671–80. immune-mediated inflammation. N Engl J Med 1995;332: 30. Daynes RA, Dudley DJ, Araneo BA. Regulation of murine 1351–62. lymphokine production in vivo. II. Dehydroepiandrosterone 49. Masi AT, Chrousos GP. Hypothalamic-pituitary-adrenal-glu- is a natural enhancer of interleukin 2 synthesis by helper T cocorticoid axis function in rheumatoid arthritis. J Rheumatol cells. Eur J Immunol 1990;20:793–802. 1996;23:577–81. 31. Alcocer-Varela J, Alarcon-Segovia D. Decreased production of 50. Cutolo M, Foppiani L, Prete C, et al. Hypothalamic-pituitary- and response to interleukin-2 by cultured lymphocytes from adrenocortical axis function in premenopausal women with patients with systemic lupus erythematosus J Clin Invest. rheumatoid arthritis not treated with glucocorticoids. J Rheu- 1982;69:1388–92. matol 1999;26:282–8. 32. Linker-Israeli M, Bakke AC, Kitridou RC, et al. Defective 51. Crofford LJ, Kalogeras KT, Mastorakos G, et al. Circadian production of interleukin 1 and interleukin 2 in patients with relationships between interleukin (IL)-6 and hypothalamic- systemic lupus erythematosus (SLE). J Immunol 1983;130: pituitary-adrenal axis hormones: Failure of IL-6 to cause 2651–5. sustained hypercortisolism in patients with early untreated 33. Suzuki T, Suzuki N, Daynes RA, et al. Dehydroepiandros- rheumatoid arthritis. J Clin Endocrinol Metab 1997;82:1279– terone enhances IL2 production and cytotoxic effector func- 83. tion of human T cells. Clin Immunol Immunopathol 1991;61: 202–11. 52. Schlaghecke R, Kornely E, Wollenhaupt J, et al. Glucocorticoid receptors in rheumatoid arthritis. Arthritis Rheum 1992;35: 34. Lahita RG, Bradlow HL, Kunkel HG, et al. Alterations of 740–4. estrogen metabolism in systemic lupus erythematosus. Arthri- tis Rheum 1979;22:1195–8. 53. Masi AT, Josipovic DB, Jefferson WE. Low adrenal androgen- ic-anabolic steroids in women with rheumatoid arthritis (RA): 35. Lahita RG, Bradlow HL, Kunkel HG, et al. Increased 16 Gas-liquid chromatographic studies of RA patients and alpha-hydroxylation of estradiol in systemic lupus erythema- matched normal control women indicating decreased 11- tosus. J Clin Endocrinol Metab 1981;53:174–8. deoxy-17- excretion. Semin Arthritis Rheum 1984; 36. Lahita RG, Bradlow HL, Fishman J, et al. Estrogen metabolism 14:1–23. in systemic lupus erythematosus: Patients and family mem- 54. Cutolo M, Masi AT. Do androgens influence the pathophysi- bers. Arthritis Rheum 1982;25:843–56. ology of rheumatoid arthritis? Facts and hypotheses. J Rheu- 37. Zhu BT, Conney AH. Review: Functional role of estrogen matol 1998;25:1041–7. metabolism in target cells: Review and perspectives. Carcino- genesis 1998;19:1–27. 55. Masi AT, Chrousos GP, Bornstein SR. Enigmas of adrenal androgen and glucocorticoid dissociation in premenopausal 38. Fishman J, Martucci C. Biological properties of 16 alpha- onset rheumatoid arthritis. J Rheumatol 1999;26:247–50. hydroxyestrone: Implications in estrogen physiology and pathophysiology. J Clin Endocrinol Metab 1980;51:611–15. 56. Ehrhart-Bornstein M, Hinson JP, Bornstein SR, et al. Intraad- renal interactions in the regulation of adrenocortical steroido- 39. Bucala R, Fishman J, Cerami A. Formation of covalent adducts genesis. Endocr Rev 1998;19:101–43. between cortisol and 16 alpha-hydroxyestrone and protein: Possible role in the pathogenesis of cortisol toxicity and 57. Nussdorfer GG, Mazzocchi G. Immune-endocrine interactions systemic lupus erythematosus. Proc Natl Acad Sci 1982;79: in the mammalian adrenal gland: Facts and hypotheses. Int 3320–4. Rev Cytol 1998;183:143–84. 40. Lahita RG, Bradlow HL. Klinefelter’s syndrome: Hormone 58. Reichlin S. Neuroendocrine-immune interactions. N Engl metabolism in hypogonadal males with systemic lupus ery- J Med 1993;329:1246–53. thematosus. J Rheumatol 1987;14(Suppl 13):154–7. 59. Hennebold JD, Daynes RA. Regulation of macrophage dehy- 41. Lamberts SW, Verleun T, Hofland L, et al. Differences in the droepiandrosterone sulfate metabolism by inflammatory cy- interaction between dopamine and estradiol on prolactin tokines. Endocrinology 1994;135:67–75. release by cultured normal and tumorous human pituitary 60. Straub RH, Konecna L, Hrach S, et al. Serum dehydroepi- cells. J Clin Endocrinol Metab 1986;63:1342–7. androsterone (DHEA) and DHEA sulfate are negatively cor- 42. Shupnik MA, Pitt LK, Soh AY, et al. Selective expression of related with serum interleukin-6 (IL-6), and DHEA inhibits and beta isoforms in human pituitary IL-6 secretion from mononuclear cells in man in vitro: Possible tumors. J Clin Endocrinol Metab 1998;83:3965–72. link between endocrinosenescence and immunosenescence. 43. Fishman J, Tulchinsky D. Suppression of prolactin secretion in J Clin Endocrinol Metab 1998;83:2012–7. normal young women by 2-hydroxyestrone. Science 1980;210: 61. Kimura M, Tanaka S, Yamada Y, et al. Dehydroepiandros- 73–4. terone decreases serum tumor necrosis factor-alpha and re- April 2002 AUTOIMMUNITY, DHEA, AND STRESS 43

stores insulin sensitivity: Independent effect from secondary 67. Rosen A, Casciola-Rosen L. Autoantigens as substrates for weight reduction in genetically obese Zucker fatty rats. Endo- apoptotic proteases: Implications for the pathogenesis of sys- crinology 1998;139:3249–53. temic autoimmune disease. Cell Death Differ 1999;6:6–12. 62. Padgett DA, Loria RM. Endocrine regulation of murine mac- 68. Schwartzman RA, Cidlowski JA. Apoptosis: The biochemistry rophage function: Effects of dehydroepiandrosterone, andro- and molecular biology of programmed cell death. Endocr Rev stenediol, and androstenetriol. J Neuroimmunol 1998;84:61–8. 1993;14:133–51. 63. Cutolo M, Accardo S, Villaggio et al. Androgen and estrogen 69. Hedman M, Nilsson E, de la Torre B. Low blood and synovial receptors are present in primary cultures of human synovial fluid levels of sulpho-conjugated steroids in rheumatoid ar- thritis. Clin Exp Rheumatol 1992;10:25–30. macrophages. J Clin Endocrinol Metab 1996;81:8320–7. 70. van Vollenhoven RF, Engleman EG, McGuire JL. An open 64. Vaishnaw AK, McNally JD, Elkon KB. Apoptosis in the study of dehydroepiandrosterone in systemic lupus erythem- rheumatic diseases. Arthritis Rheum 1997;40:1917–27. atosus. Arthritis Rheum 1994;37:1305–10. 65. Cutolo M, Sulli A, Barone A, et al. Sex hormones, proto- 71. van Vollenhoven RF, Engleman EG, McGuire JL. Dehydroepi- oncogene expression and apoptosis: Their effects on rheuma- androsterone in systemic lupus erythematosus. Results of a toid synovial tissue. Clin Exp Rheumatol 1996;14:87–94. double-blind, placebo-controlled, randomized . 66. Seki M, Ushiyama C, Seta N, et al. Apoptosis of lymphocytes Arthritis Rheum 1995;38:1826–31. induced by glucocorticoids and relationship to therapeutic 72. Petri M, Lahita R, McGuire J, et al. Results of the GL701 efficacy in patients with systemic lupus erythematosus. Ar- (DHEA) Multicenter Steroid-Sparing SLE Study [abstract]. thritis Rheum 1998;41:823–30. Arthritis Rheum 1997;40(Suppl):S327.