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Spotlight on DHEA: A marker for progression of HIV infection?
Spotlight on DHEA: A marker for progression of HIV infection? Abbreviations: D H E A = d e h y d r o e p i a n d r o s t e r o n e ;
he 19-carbon adrenal steroid DHEA has seen a recent resurgence of its reputation as a "fountain of youth ''1 as well as new popularity as a potential treatment for AIDS. 2 Predominantly circulating in its sulfate-conjugated form, DHEA is the most abundant steroid in human blood. DHEA is produced in huge quantities by the fetal adrenal gland; high neonatal blood levels fall precipitously to near zero shortly after birth and then begin to rise again at adrenarche at age 7 or 8 years. After peaking in the third decade of life, DHEA levels fall throughout adulthood, ultimately to only 10% to 20% of peak levels. 3'4 DHEA has been long classified as a weak androgen, and the hormonal effects of DHEA are traceable to its conversion to the classic active androgens (testosterone and dihydrotesterone)5 or estrogens. 6 Despite decades of investigation, evidence of DHEA having any direct hormonal effect has proven elusive. Nevertheless, blood levels of this steroid have been consistently inversely correlated with a host of serious illnesses, including breast cancer and heart disease] Further, two recent clinical trials have demonstrated substantial benefits when DHEA has been used in replacement therapy in the agedS'9; these have included improvements in several indices of immune system function.8 Also, a number of recent reports have suggested a specific role for DHEA as an immune system regulator in rodent models; specifically, DHEA enhanced the production of IL-2 by isolated activated mouse T cells, 1° an action antagonistic to IL-2 suppression by glucocorticoids. The same group also reported similar effects on human T cells in vitro. 11 In one study of mouse thymocytes12 this IL-2 enhancement has been correlated with specific DHEA binding of a type characteristic of classical steroid receptors. Although such effects have only been demonstrated in vivo in rodents (where levels of DHEA are only a small fraction of those found in human beings), a model has been proposed in which DHEA plays a
T
J Lab Clin Med 1996;127:522-3. Copyright © 1996 by Mosby-Year Book, Inc. 0022-2143/96 $5.00 + 0 5/1/72431
522
IL-2 = i n t e r l e u k i n - 2
central role in human AIDS. 13 According to this hypothesis, the concomitant increase in cortisol and decrease in DHEA that is seen during the progression of HIV infection to AIDS in human patients shifts the immune system's production of regulatory cytokines toward suppression of cell-mediated immunity and promotion of viral replication. In addition, evidence of in vitro activity against HIV has sparked interest in the clinical use of DHEA in the treatment of AIDS. 2 Interest in DHEA and AIDS has also focused on the potential of DHEA as a prognosticator of HIV disease progression) 4'15 However, a major difficulty in evaluating the significance of declining DHEA levels is presented by the nature of available AIDS study populations--that is, they are mostly composed of homosexual males with a host of other attendant variables, including multiple illicit drug abuse and multiple sexually transmitted diseases. In this issue of the JOURNAL, Chatterton et al. 16 provide an important new perspective on DHEA measurements to gain insights into its possible role in the progression of HIV disease and its utility in assessment of clinical status. These authors present the results of a longitudinal study of 16 HIV-1 infected heterosexual men with hemophilia. The men were followed for up to 11 years, with blood levels of CD4 + cells and of DHEA and other selected hormones measured. Over the course of the study, severe illnesses developed in several of the subjects, and these illnesses were accompanied by drastic reductions in CD4 + cell counts that were presaged by falling DHEA levels. However, similar observations in patients who progressed to AIDS and in those who developed other severe illnesses led the authors to conclude that the observed changes in DHEA were nonspecific. If the careful observations of Chatterton et al. 16 in this unique population may be extended to HIVinfected patients in general, they may well explain the absence of any significant signs of inhibition or reversal of disease progression (e.g., improvement in CD4+-lymphocyte counts) thus far seen in preliminary clinical trials. 2 It would thus appear that the DHEA decrease seen in the progression of HIV
J Lab Clin Med Volume 127, Number 6
Editorial
d i s e a s e is s e c o n d a r y to t h e d i s e a s e p r o c e s s itself. T h e r e f o r e , t h e clinical utility o f D H E A t r e a t m e n t o f p a t i e n t s w i t h A I D S m a y b e l i m i t e d to its f u n c t i o n as a n a n d r o g e n p r e c u r s o r , in w h i c h r o l e it m a y h e l p to offset t h e s e c o n d a r y p h y s i o l o g i c a n d p s y c h o l o g i c effects o f t h e h y p o g o n a d i s m so f r e q u e n t l y s e e n in p a t i e n t s w i t h A I D S . 17 J O E L B R I N D , PhD
Department of Natural Sciences Baruch College The City University of New York New York, N Y 10010 Orentreich Foundation for the Advancement of Science. Inc. Biomedical Research Station Cold Spring-on-Hudson, N Y 10516 REFERENCES
1. Carey B. Hooked on youth. Health 1995;Nov/Dec:68-74. 2. Dyner TS, Lang W, Geaga J, et al. An open-label doseescalation trial of oral dehydroepiandrosterone tolerance and pharmacokinetics in patients with HIV disease. Journal of Acquired Immune Deficiency Syndrome 1993;6:45965. 3. Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984;59:551-5. 4. Orentreich N, Brind JL, Vogelman JH, Andres R, Baldwin H. Long-term longitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men. J Clin Endocrinol Metab 1992;75:1002-4. 5. Mertola J, Yen SSC. The effects of dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab 1990;71:696-704. 6. Khaw KT, Tazuke S, Barrett-Conner E. Cigarette smoking and levels of adrenal androgens in postmenopausal women. N Engl J Med 1988;318:1705-9.
525
7. Casson PR, Buster JE. DHEA administration to humans: panacea or palaver? Semin Reprod Endocrinol 1995;13:24756. 8. Casson PR, Andersen RN, Herrod HG, et al. Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women. Am J Obstet Gynecol 1993;169:1536-9. 9. Morales AJ, Nolan J, Nelson JC, Yen SSC. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994; 78:1360-7. 10. Daynes RA, Dudley D J, Araneo BA. Regulation of murine lymphokine production in vivo: dehydroepiandrosterone is a natural enhancer of interleukin 2 synthesis by helper T cells. Eur J Immunol 1990;20:793-802. 11. Suzuki T, Suzuki N, Daynes RA, Engleman EG. Dehydroepiandrosterone enhances IL-2 production and cytotoxic eflector function of human T cells. Ctin Immunol Immunopathol 1991;61:202-11. 12. Meikle AW, Dorchuck RW, Araneo BA, et al. The presence of a dehydroepiandrosterone-specific receptor binding complex in routine T cells. J Steroid Biochem Mol Biol 1992;42: 293-304. 13. Clerici M, Bevilacqua M, Vago T, Villa ML, Shearer GM, Norbiato G. An immunoendocrinological hypothesis of HIV infection. Lancet 1994;343:1552-3. 14. Merril R, Harrington G, Sunderland T. Plasma dehydroepiandrosterone levels in HIV infection. JAMA 1989;261: 1149. 15. Mulder JW, JosFrissen PH, Krijnen P, et al. Dehydroepiandrosterone as predictor for progression to AIDS in asymptomatic human immunodeficiency virus-infected men. J Infect Dis 1992;165:413-8. 16. Chatteron RT Jr, Green D, Harris S, Grossman A, Hechter O. Longitudinal study of adrenal steroids in a cohort of HIV infected hemophiliacs. J Lab Clin Med 1996;127:545-52. 17. Laudat A, Blum L, Gu6chot, et al. Changes in systemic gonadal steroids in asymptomatic human immunodeficiency virus-infected men: relationship with the CD4 cell counts. Eur J Endocrinol 1995;133:418-24.
he 19-carbon adrenal steroid DHEA has seen a recent resurgence of its reputation as a "fountain of youth ''1 as well as new popularity as a potential treatment for AIDS. 2 Predominantly circulating in its sulfate-conjugated form, DHEA is the most abundant steroid in human blood. DHEA is produced in huge quantities by the fetal adrenal gland; high neonatal blood levels fall precipitously to near zero shortly after birth and then begin to rise again at adrenarche at age 7 or 8 years. After peaking in the third decade of life, DHEA levels fall throughout adulthood, ultimately to only 10% to 20% of peak levels. 3'4 DHEA has been long classified as a weak androgen, and the hormonal effects of DHEA are traceable to its conversion to the classic active androgens (testosterone and dihydrotesterone)5 or estrogens. 6 Despite decades of investigation, evidence of DHEA having any direct hormonal effect has proven elusive. Nevertheless, blood levels of this steroid have been consistently inversely correlated with a host of serious illnesses, including breast cancer and heart disease] Further, two recent clinical trials have demonstrated substantial benefits when DHEA has been used in replacement therapy in the agedS'9; these have included improvements in several indices of immune system function.8 Also, a number of recent reports have suggested a specific role for DHEA as an immune system regulator in rodent models; specifically, DHEA enhanced the production of IL-2 by isolated activated mouse T cells, 1° an action antagonistic to IL-2 suppression by glucocorticoids. The same group also reported similar effects on human T cells in vitro. 11 In one study of mouse thymocytes12 this IL-2 enhancement has been correlated with specific DHEA binding of a type characteristic of classical steroid receptors. Although such effects have only been demonstrated in vivo in rodents (where levels of DHEA are only a small fraction of those found in human beings), a model has been proposed in which DHEA plays a
T
J Lab Clin Med 1996;127:522-3. Copyright © 1996 by Mosby-Year Book, Inc. 0022-2143/96 $5.00 + 0 5/1/72431
522
IL-2 = i n t e r l e u k i n - 2
central role in human AIDS. 13 According to this hypothesis, the concomitant increase in cortisol and decrease in DHEA that is seen during the progression of HIV infection to AIDS in human patients shifts the immune system's production of regulatory cytokines toward suppression of cell-mediated immunity and promotion of viral replication. In addition, evidence of in vitro activity against HIV has sparked interest in the clinical use of DHEA in the treatment of AIDS. 2 Interest in DHEA and AIDS has also focused on the potential of DHEA as a prognosticator of HIV disease progression) 4'15 However, a major difficulty in evaluating the significance of declining DHEA levels is presented by the nature of available AIDS study populations--that is, they are mostly composed of homosexual males with a host of other attendant variables, including multiple illicit drug abuse and multiple sexually transmitted diseases. In this issue of the JOURNAL, Chatterton et al. 16 provide an important new perspective on DHEA measurements to gain insights into its possible role in the progression of HIV disease and its utility in assessment of clinical status. These authors present the results of a longitudinal study of 16 HIV-1 infected heterosexual men with hemophilia. The men were followed for up to 11 years, with blood levels of CD4 + cells and of DHEA and other selected hormones measured. Over the course of the study, severe illnesses developed in several of the subjects, and these illnesses were accompanied by drastic reductions in CD4 + cell counts that were presaged by falling DHEA levels. However, similar observations in patients who progressed to AIDS and in those who developed other severe illnesses led the authors to conclude that the observed changes in DHEA were nonspecific. If the careful observations of Chatterton et al. 16 in this unique population may be extended to HIVinfected patients in general, they may well explain the absence of any significant signs of inhibition or reversal of disease progression (e.g., improvement in CD4+-lymphocyte counts) thus far seen in preliminary clinical trials. 2 It would thus appear that the DHEA decrease seen in the progression of HIV
J Lab Clin Med Volume 127, Number 6
Editorial
d i s e a s e is s e c o n d a r y to t h e d i s e a s e p r o c e s s itself. T h e r e f o r e , t h e clinical utility o f D H E A t r e a t m e n t o f p a t i e n t s w i t h A I D S m a y b e l i m i t e d to its f u n c t i o n as a n a n d r o g e n p r e c u r s o r , in w h i c h r o l e it m a y h e l p to offset t h e s e c o n d a r y p h y s i o l o g i c a n d p s y c h o l o g i c effects o f t h e h y p o g o n a d i s m so f r e q u e n t l y s e e n in p a t i e n t s w i t h A I D S . 17 J O E L B R I N D , PhD
Department of Natural Sciences Baruch College The City University of New York New York, N Y 10010 Orentreich Foundation for the Advancement of Science. Inc. Biomedical Research Station Cold Spring-on-Hudson, N Y 10516 REFERENCES
1. Carey B. Hooked on youth. Health 1995;Nov/Dec:68-74. 2. Dyner TS, Lang W, Geaga J, et al. An open-label doseescalation trial of oral dehydroepiandrosterone tolerance and pharmacokinetics in patients with HIV disease. Journal of Acquired Immune Deficiency Syndrome 1993;6:45965. 3. Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984;59:551-5. 4. Orentreich N, Brind JL, Vogelman JH, Andres R, Baldwin H. Long-term longitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men. J Clin Endocrinol Metab 1992;75:1002-4. 5. Mertola J, Yen SSC. The effects of dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab 1990;71:696-704. 6. Khaw KT, Tazuke S, Barrett-Conner E. Cigarette smoking and levels of adrenal androgens in postmenopausal women. N Engl J Med 1988;318:1705-9.
525
7. Casson PR, Buster JE. DHEA administration to humans: panacea or palaver? Semin Reprod Endocrinol 1995;13:24756. 8. Casson PR, Andersen RN, Herrod HG, et al. Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women. Am J Obstet Gynecol 1993;169:1536-9. 9. Morales AJ, Nolan J, Nelson JC, Yen SSC. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994; 78:1360-7. 10. Daynes RA, Dudley D J, Araneo BA. Regulation of murine lymphokine production in vivo: dehydroepiandrosterone is a natural enhancer of interleukin 2 synthesis by helper T cells. Eur J Immunol 1990;20:793-802. 11. Suzuki T, Suzuki N, Daynes RA, Engleman EG. Dehydroepiandrosterone enhances IL-2 production and cytotoxic eflector function of human T cells. Ctin Immunol Immunopathol 1991;61:202-11. 12. Meikle AW, Dorchuck RW, Araneo BA, et al. The presence of a dehydroepiandrosterone-specific receptor binding complex in routine T cells. J Steroid Biochem Mol Biol 1992;42: 293-304. 13. Clerici M, Bevilacqua M, Vago T, Villa ML, Shearer GM, Norbiato G. An immunoendocrinological hypothesis of HIV infection. Lancet 1994;343:1552-3. 14. Merril R, Harrington G, Sunderland T. Plasma dehydroepiandrosterone levels in HIV infection. JAMA 1989;261: 1149. 15. Mulder JW, JosFrissen PH, Krijnen P, et al. Dehydroepiandrosterone as predictor for progression to AIDS in asymptomatic human immunodeficiency virus-infected men. J Infect Dis 1992;165:413-8. 16. Chatteron RT Jr, Green D, Harris S, Grossman A, Hechter O. Longitudinal study of adrenal steroids in a cohort of HIV infected hemophiliacs. J Lab Clin Med 1996;127:545-52. 17. Laudat A, Blum L, Gu6chot, et al. Changes in systemic gonadal steroids in asymptomatic human immunodeficiency virus-infected men: relationship with the CD4 cell counts. Eur J Endocrinol 1995;133:418-24.