Dehydroepiandrosterone Replacement Therapy

ABSTRACT

Dehydroepiandrosterone (DHEA) replacement therapy has attracted considerable attention over recent years. Significant beneficial effects of DHEA replacement have been reported in patients representing the pathophysiological model of complete DHEA deficiency, in other words, adrenal insufficiency (AI). This includes effects on well-being, energy levels, mood, and libido, which is usually impaired in AI, particularly in female patients. DHEA exerts its action mainly indirectly via downstream metabolism to sex steroids, and conversion to active androgens is likely to play a major role. In addition, DHEA has well-described neurosteroidal properties, and by exerting anti-gamma aminobutyric acid(GABA)ergic action it may have antidepressive potential. Other patient groups that may benefit from DHEA replacement are patients receiving chronic exogenous glucocorticoid treatment, which invariably leads to persistent suppression of DHEA production. In patients with systemic lupus erythematosus, DHEA has been shown to reduce disease activity and has a glucocorticoid-sparing effect. However, caution is required regarding DHEA treatment in individuals with only a relative decline in circulating DHEA levels. This particularly includes the physiological decline of DHEA and its sulfate ester observed with aging. Even the elderly maintain circulating levels of DHEA that are orders of magnitude higher than what is observed in AI. Even physiological menopause does not necessarily lead to a decrease in circulating androgens while estrogen production invariably ceases. Current evidence from randomized, controlled trials in healthy elderly persons including several cohorts of postmenopausal women does not justify the use of DHEA. However, DHEA may be a suitable option for androgen replacement in women with established androgen deficiency, for example, bilateral oophorectomy and premature menopause.

KEYWORDS

DHEA - dehydroepiandrosterone - replacement - adrenal insufficiency - androgen

REFERENCES

• 1 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
• 2 Palmert M R, Hayden D L, Mansfield M J et al.. The longitudinal study of adrenal maturation during gonadal suppression: evidence that adrenarche is a gradual process.  J Clin Endocrinol Metab. 2001;  86 4536-4542
• 3 Reiter E O, Fuldauer V G, Root A W. Secretion of the adrenal androgen, dehydroepiandrosterone sulfate, during normal infancy, childhood, and adolescence, in sick infants, and in children with endocrinologic abnormalities.  J Pediatr. 1977;  90 766-770
• 4 Sklar C A, Kaplan S L, Grumbach M M. Evidence for dissociation between adrenarche and gonadarche: studies in patients with idiopathic precocious puberty, gonadal dysgenesis, isolated gonadotropin deficiency, and constitutionally delayed growth and adolescence.  J Clin Endocrinol Metab. 1980;  51 548-556
• 5 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
• 6 Suzuki T, Sasano H, Takeyama J et al.. Developmental changes in steroidogenic enzymes in human postnatal adrenal cortex: immunohistochemical studies.  Clin Endocrinol (Oxf). 2000;  53 739-747
• 7 Auchus R J, Rainey W E. Adrenarche-physiology, biochemistry and human disease.  Clin Endocrinol (Oxf). 2004;  60 288-296
• 8 Bassett M H, Suzuki T, Sasano H et al.. The orphan nuclear receptor NGFIB regulates transcription of 3beta-hydroxysteroid dehydrogenase: Implications for the control of adrenal functional zonation.  J Biol Chem. 2004;  279 37622-37630
• 9 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
• 10 Orentreich N, Brind J L, Vogelman J H, Andres R, Baldwin H. Long-term longitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men.  J Clin Endocrinol Metab. 1992;  75 1002-1004
• 11 Laughlin G A, Barrett-Connor E. Sexual dimorphism in the influence of advanced aging on adrenal hormone levels: the Rancho Bernardo Study.  J Clin Endocrinol Metab. 2000;  85 3561-3568
• 12 Parker Jr C R, Mixon R L, Brissie R M, Grizzle W E. Aging alters zonation in the adrenal cortex of men.  J Clin Endocrinol Metab. 1997;  82 3898-3901
• 13 Liu C H, Laughlin G A, Fischer U G, Yen S S. Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in postmenopausal women: evidence for a reduced 17,20-desmolase enzymatic activity.  J Clin Endocrinol Metab. 1990;  71 900-906
• 14 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
• 15 Sulcova J, Hill M, Hampl R, Starka L. Age and sex related differences in serum levels of unconjugated dehydroepiandrosterone and its sulphate in normal subjects.  J Endocrinol. 1997;  154 57-62
• 16 Khaw K T. Dehydroepiandrosterone, dehydroepiandrosterone sulphate and cardiovascular disease.  J Endocrinol. 1996;  150(Suppl) S149-S153
• 17 Thomas G, Frenoy N, Legrain S et al.. Serum dehydroepiandrosterone sulfate levels as an individual marker.  J Clin Endocrinol Metab. 1994;  79 1273-1276
• 18 Cutler Jr G B, Glenn M, Bush M et al.. Adrenarche: a survey of rodents, domestic animals, and primates.  Endocrinology. 1978;  103 2112-2118
• 19 Svec F, Porter J R. The actions of exogenous dehydroepiandrosterone in experimental animals and humans.  Proc Soc Exp Biol Med. 1998;  218 174-191
• 20 Auchus R J, Lee T C, Miller W L. Cytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer.  J Biol Chem. 1998;  273 3158-3165
• 21 Geller D H, Auchus R J, Mendonca B B, Miller W L. The genetic and functional basis of isolated 17,20-lyase deficiency.  Nat Genet. 1997;  17 201-205
• 22 Arlt W, Justl H G, Callies F et al.. Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression.  J Clin Endocrinol Metab. 1998;  83 1928-1934
• 23 Arlt W, Haas J, Callies F et al.. Biotransformation of oral dehydroepiandrosterone in elderly men: significant increase in circulating estrogens.  J Clin Endocrinol Metab. 1999;  84 2170-2176
• 24 Labrie F, Belanger A, Cusan L, Candas B. Physiological changes in dehydroepiandrosterone are not reflected by serum levels of active androgens and estrogens but of their metabolites: intracrinology.  J Clin Endocrinol Metab. 1997;  82 2403-2409
• 25 Giagulli V A, Verdonck L, Giorgino R, Vermeulen A. Precursors of plasma androstanediol- and androgen-glucuronides in women.  J Steroid Biochem. 1989;  33 935-940
• 26 Martel C, Melner M H, Gagne D, Simard J, Labrie F. Widespread tissue distribution of steroid sulfatase, 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase (3 beta-HSD), 17 beta-HSD 5 alpha-reductase and aromatase activities in the rhesus monkey.  Mol Cell Endocrinol. 1994;  104 103-111
• 27 Jakob F, Siggelkow H, Homann D et al.. Local estradiol metabolism in osteoblast- and osteoclast-like cells.  J Steroid Biochem Mol Biol. 1997;  61 167-174
• 28 English M A, Hughes S V, Kane K F et al.. Oestrogen inactivation in the colon: analysis of the expression and regulation of 17beta-hydroxysteroid dehydrogenase isozymes in normal colon and colonic cancer.  Br J Cancer. 2000;  83 550-558
• 29 Padgett D A, Loria R M. In vitro potentiation of lymphocyte activation by dehydroepiandrosterone, androstenediol, and androstenetriol.  J Immunol. 1994;  153 1544-1552
• 30 Martin C, Ross M, Chapman K E et al.. CYP7B generates a selective estrogen receptor beta agonist in human prostate.  J Clin Endocrinol Metab. 2004;  89 2928-2935
• 31 Weihua Z, Lathe R, Warner M, Gustafsson J A. An endocrine pathway in the prostate, ERbeta, AR, 5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate growth.  Proc Natl Acad Sci USA. 2002;  99 13589-13594
• 32 Allolio B, Arlt W. DHEA treatment: myth or reality?.  Trends Endocrinol Metab. 2002;  13 288-294
• 33 Corpechot C, Robel P, Axelson M, Sjovall J, Baulieu E E. Characterization and measurement of dehydroepiandrosterone sulfate in rat brain.  Proc Natl Acad Sci USA. 1981;  78 4704-4707
• 34 Compagnone N A, Bulfone A, Rubenstein J L, Mellon S H. Steroidogenic enzyme P450c17 is expressed in the embryonic central nervous system.  Endocrinology. 1995;  136 5212-5223
• 35 Steckelbroeck S, Heidrich D D, Stoffel-Wagner B et al.. Characterization of aromatase cytochrome P450 activity in the human temporal lobe.  J Clin Endocrinol Metab. 1999;  84 2795-2801
• 36 Steckelbroeck S, Stoffel-Wagner B, Reichelt R et al.. Characterization of 17beta-hydroxysteroid dehydrogenase activity in brain tissue: testosterone formation in the human temporal lobe.  J Neuroendocrinol. 1999;  11 457-464
• 37 Steckelbroeck S, Watzka M, Reichelt R et al.. Characterization of the 5alpha-reductase-3alpha-hydroxysteroid dehydrogenase complex in the human brain.  J Clin Endocrinol Metab. 2001;  86 1324-1331
• 38 Steckelbroeck S, Watzka M, Lutjohann D et al.. Characterization of the dehydroepiandrosterone (DHEA) metabolism via oxysterol 7alpha-hydroxylase and 17-ketosteroid reductase activity in the human brain.  J Neurochem. 2002;  83 713-726
• 39 Steckelbroeck S, Nassen A, Ugele B et al.. Steroid sulfatase (STS) expression in the human temporal lobe: enzyme activity, mRNA expression and immunohistochemistry study.  J Neurochem. 2004;  89 403-417
• 40 Zwain I H, Yen S S. Neurosteroidogenesis in astrocytes, oligodendrocytes, and neurons of cerebral cortex of rat brain.  Endocrinology. 1999;  140 3843-3852
• 41 Zwain I H, Yen S S. Dehydroepiandrosterone: biosynthesis and metabolism in the brain.  Endocrinology. 1999;  140 880-887
• 42 Bergeron R, de Montigny C, Debonnel G. Potentiation of neuronal NMDA response induced by dehydroepiandrosterone and its suppression by progesterone: effects mediated via sigma receptors.  J Neurosci. 1996;  16 1193-1202
• 43 Majewska M D, Demirgoren S, Spivak C E, London E D. The neurosteroid dehydroepiandrosterone sulfate is an allosteric antagonist of the GABAA receptor.  Brain Res. 1990;  526 143-146
• 44 Demirgoren S, Majewska M D, Spivak C E, London E D. Receptor binding and electrophysiological effects of dehydroepiandrosterone sulfate, an antagonist of the GABAA receptor.  Neuroscience. 1991;  45 127-135
• 45 Compagnone N A, Mellon S H. Dehydroepiandrosterone: a potential signalling molecule for neocortical organization during development.  Proc Natl Acad Sci USA. 1998;  95 4678-4683
• 46 Suzuki M, Wright L S, Marwah P, Lardy H A, Svendsen C N. Mitotic and neurogenic effects of dehydroepiandrosterone (DHEA) on human neural stem cell cultures derived from the fetal cortex.  Proc Natl Acad Sci USA. 2004;  101 3202-3207
• 47 Lhullier F L, Nicolaidis R, Riera N G et al.. Dehydroepiandrosterone increases synaptosomal glutamate release and improves the performance in inhibitory avoidance task.  Pharmacol Biochem Behav. 2004;  77 601-606
• 48 Aragno M, Parola S, Brignardello E et al.. Dehydroepiandrosterone prevents oxidative injury induced by transient ischemia/reperfusion in the brain of diabetic rats.  Diabetes. 2000;  49 1924-1931
• 49 Charalampopoulos I, Tsatsanis C, Dermitzaki E et al.. Dehydroepiandrosterone and allopregnanolone protect sympathoadrenal medulla cells against apoptosis via antiapoptotic Bcl-2 proteins.  Proc Natl Acad Sci USA. 2004;  101 8209-8214
• 50 Fiore C, Inman D M, Hirose S et al.. Treatment with the neurosteroid dehydroepiandrosterone promotes recovery of motor behavior after moderate contusive spinal cord injury in the mouse.  J Neurosci Res. 2004;  75 391-400
• 51 Lapchak P A, Chapman D F, Nunez S Y, Zivin J A. Dehydroepiandrosterone sulfate is neuroprotective in a reversible spinal cord ischemia model: possible involvement of GABA(A) receptors.  Stroke. 2000;  31 1953-1956
• 52 Malik A S, Narayan R K, Wendling W W et al.. A novel dehydroepiandrosterone analog improves functional recovery in a rat traumatic brain injury model.  J Neurotrauma. 2003;  20 463-476
• 53 Beck S G, Handa R J. Dehydroepiandrosterone (DHEA): a misunderstood adrenal hormone and spine-tingling neurosteroid?.  Endocrinology. 2004;  145 1039-1041
• 54 MacLusky N J, Hajszan T, Leranth C. Effects of DHEA and flutamide on hippocampal ca1 spine synapse density in male and female rats: implications for the role of androgens in maintenance of hippocampal structure.  Endocrinology. 2004;  145 4154-4161
• 55 Meikle A W, Dorchuck R W, Araneo B A et al.. The presence of a dehydroepiandrosterone-specific receptor binding complex in murine T cells.  J Steroid Biochem Mol Biol. 1992;  42 293-304
• 56 Okabe T, Haji M, Takayanagi R et al.. Up-regulation of high-affinity dehydroepiandrosterone binding activity by dehydroepiandrosterone in activated human T lymphocytes.  J Clin Endocrinol Metab. 1995;  80 2993-2996
• 57 Liu D, Dillon J S. Dehydroepiandrosterone activates endothelial cell nitric-oxide synthase by a specific plasma membrane receptor coupled to Galpha(i2,3).  J Biol Chem. 2002;  277 21379-21388
• 58 Simoncini T, Mannella P, Fornari L et al.. Dehydroepiandrosterone modulates endothelial nitric oxide synthesis via direct genomic and nongenomic mechanisms.  Endocrinology. 2003;  144 3449-3455
• 59 Williams M R, Ling S, Dawood T et al.. Dehydroepiandrosterone inhibits human vascular smooth muscle cell proliferation independent of ARs and ERs.  J Clin Endocrinol Metab. 2002;  87 176-181
• 60 Solerte S B, Fioravanti M, Vignati G et al.. Dehydroepiandrosterone sulfate enhances natural killer cell cytotoxicity in humans via locally generated immunoreactive insulin-like growth factor I.  J Clin Endocrinol Metab. 1999;  84 3260-3267
• 61 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
• 62 Suzuki T, Suzuki N, Engleman E G, Mizushima Y, Sakane T. Low serum levels of dehydroepiandrosterone may cause deficient IL-2 production by lymphocytes in patients with systemic lupus erythematosus (SLE).  Clin Exp Immunol. 1995;  99 251-255
• 63 Lovas K, Loge J H, Husebye E S. Subjective health status in Norwegian patients with Addison's disease.  Clin Endocrinol (Oxf). 2002;  56 581-588
• 64 Gurnell E M, Hunt P J, Curran S E et al.. A longer term trial of DHEA replacement in Addison's disease.  Endocrine Abstracts. 2002;  4 OC-24
• 65 Arlt W, Callies F, van Vlijmen J C et al.. Dehydroepiandrosterone replacement in women with adrenal insufficiency.  N Engl J Med. 1999;  341 1013-1020
• 66 Hunt P J, Gurnell E M, Huppert F A et al.. Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison's disease in a randomized, double blind trial.  J Clin Endocrinol Metab. 2000;  85 4650-4656
• 67 Young J, Couzinet B, Nahoul K et al.. Panhypopituitarism as a model to study the metabolism of dehydroepiandrosterone (DHEA) in humans.  J Clin Endocrinol Metab. 1997;  82 2578-2585
• 68 Callies F, Fassnacht M, van Vlijmen J C et al.. Dehydroepiandrosterone replacement in women with adrenal insufficiency: effects on body composition, serum leptin, bone turnover, and exercise capacity.  J Clin Endocrinol Metab. 2001;  86 1968-1972
• 69 Johannsson G, Burman P, Wiren L et al.. Low dose dehydroepiandrosterone affects behavior in hypopituitary androgen-deficient women: a placebo-controlled trial.  J Clin Endocrinol Metab. 2002;  87 2046-2052
• 70 Lovas K, Gebre-Medhin G, Trovik T S et al.. Replacement of dehydroepiandrosterone in adrenal failure: no benefit for subjective health status and sexuality in a 9-month, randomized, parallel group clinical trial.  J Clin Endocrinol Metab. 2003;  88 1112-1118
• 71 Arlt W, Allolio B. Adrenal insufficiency.  Lancet. 2003;  361 1881-1893
• 72 Morales A J, Nolan J J, Nelson J C, Yen S S. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age.  J Clin Endocrinol Metab. 1994;  78 1360-1367
• 73 Wolf O T, Neumann O, Hellhammer D H et al.. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men.  J Clin Endocrinol Metab. 1997;  82 2363-2367
• 74 Wolf O T, Naumann E, Hellhammer D H, Kirschbaum C. Effects of dehydroepiandrosterone replacement in elderly men on event-related potentials, memory, and well-being.  J Gerontol A Biol Sci Med Sci. 1998;  53 M385-M390
• 75 Arlt W, Callies F, Koehler I et al.. Dehydroepiandrosterone supplementation in healthy men with an age-related decline of dehydroepiandrosterone secretion.  J Clin Endocrinol Metab. 2001;  86 4686-4692
• 76 Van Niekerk J K, Huppert F A, Herbert J. Salivary cortisol and DHEA: association with measures of cognition and well-being in normal older men, and effects of three months of DHEA supplementation.  Psychoneuroendocrinology. 2001;  26 591-612
• 77 Baulieu E E, Thomas G, Legrain S et al.. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: contribution of the DHEAge Study to a sociobiomedical issue.  Proc Natl Acad Sci USA. 2000;  97 4279-4284
• 78 Kahn A J, Halloran B. Dehydroepiandrosterone supplementation and bone turnover in middle-aged to elderly men.  J Clin Endocrinol Metab. 2002;  87 1544-1549
• 79 Villareal D T, Holloszy J O, Kohrt W M. Effects of DHEA replacement on bone mineral density and body composition in elderly women and men.  Clin Endocrinol (Oxf). 2000;  53 561-568
• 80 Morales A J, Haubrich R H, Hwang J Y, Asakura H, Yen S S. The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women.  Clin Endocrinol (Oxf). 1998;  49 421-432
• 81 Yen S S, Morales A J, Khorram O. Replacement of DHEA in aging men and women. Potential remedial effects.  Ann N Y Acad Sci. 1995;  774 128-142
• 82 Casson P R, Faquin L C, Stentz F B et al.. Replacement of dehydroepiandrosterone enhances T-lymphocyte insulin binding in postmenopausal women.  Fertil Steril. 1995;  63 1027-1031
• 83 Diamond P, Cusan L, Gomez J L, Belanger A, Labrie F. Metabolic effects of 12-month percutaneous dehydroepiandrosterone replacement therapy in postmenopausal women.  J Endocrinol. 1996;  150(Suppl) S43-S50
• 84 Kawano H, Yasue H, Kitagawa A et al.. Dehydroepiandrosterone supplementation improves endothelial function and insulin sensitivity in men.  J Clin Endocrinol Metab. 2003;  88 3190-3195
• 85 Christiansen J J, Gravholt C H, Fisker S et al.. Dehydroepiandrosterone supplementation in women with adrenal failure: impact on twenty-four hour GH secretion and IGF-related parameters.  Clin Endocrinol (Oxf). 2004;  60 461-469
• 86 Wolkowitz O M, Reus V I, Keebler A et al.. Double-blind treatment of major depression with dehydroepiandrosterone.  Am J Psychiatry. 1999;  156 646-649
• 87 Bloch M, Schmidt P J, Danaceau M A, Adams L F, Rubinow D R. Dehydroepiandrosterone treatment of midlife dysthymia.  Biol Psychiatry. 1999;  45 1533-1541
• 88 Sugino M, Ohsawa N, Ito T et al.. A pilot study of dehydroepiandrosterone sulfate in myotonic dystrophy.  Neurology. 1998;  51 586-589
• 89 Strous R D, Maayan R, Lapidus R et al.. Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia.  Arch Gen Psychiatry. 2003;  60 133-141
• 90 Reiter W J, Pycha A, Schatzl G et al.. Dehydroepiandrosterone in the treatment of erectile dysfunction: a prospective, double-blind, randomized, placebo-controlled study.  Urology. 1999;  53 590-594
• 91 Arlt W. Management of the androgen-deficient woman.  Growth Horm IGF Res. 2003;  13(Suppl) S85-S89
• 92 Shifren J L, Braunstein G D, Simon J A et al.. Transdermal testosterone treatment in women with impaired sexual function after oophorectomy.  N Engl J Med. 2000;  343 682-688
• 93 Labrie F, Luu-The V, Labrie C et al.. Endocrine and intracrine sources of androgens in women: inhibition of breast cancer and other roles of androgens and their precursor dehydroepiandrosterone.  Endocr Rev. 2003;  24 152-182
• 94 Wolkowitz O M, Kramer J H, Reus V I et al.. DHEA treatment of Alzheimer's disease: a randomized, double-blind, placebo-controlled study.  Neurology. 2003;  60 1071-1076
• 95 Arlt W, Callies F, Allolio B. DHEA replacement in women with adrenal insufficiency-pharmacokinetics, bioconversion and clinical effects on well-being, sexuality and cognition.  Endocr Res. 2000;  26 505-511
• 96 Kline M D, Jaggers E D. Mania onset while using dehydroepiandrosterone.  Am J Psychiatry. 1999;  156 971
• 97 Markowitz J S, Carson W H, Jackson C W. Possible dihydroepiandrosterone-induced mania.  Biol Psychiatry. 1999;  45 241-242
• 98 Suzuki T, Suzuki N, Daynes R A, Engleman E G. Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells.  Clin Immunol Immunopathol. 1991;  61 202-211
• 99 Gordon C M, LeBoff M S, Glowacki J. Adrenal and gonadal steroids inhibit IL-6 secretion by human marrow cells.  Cytokine. 2001;  16 178-186
• 100 Evans T G, Judd M E, Dowell T et al.. The use of oral dehydroepiandrosterone sulfate as an adjuvant in tetanus and influenza vaccination of the elderly.  Vaccine. 1996;  14 1531-1537
• 101 Danenberg H D, Ben Yehuda A, Zakay-Rones Z, Gross D J, Friedman G. Dehydroepiandrosterone treatment is not beneficial to the immune response to influenza in elderly subjects.  J Clin Endocrinol Metab. 1997;  82 2911-2914
• 102 Degelau J, Guay D, Hallgren H. The effect of DHEAS on influenza vaccination in aging adults.  J Am Geriatr Soc. 1997;  45 747-751
• 103 Chang D M, Lan J L, Lin H Y, Luo S F. Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus: a multicenter randomized, double-blind, placebo-controlled trial.  Arthritis Rheum. 2002;  46 2924-2927
• 104 Petri M A, Lahita R G, Van Vollenhoven R F et al.. Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial.  Arthritis Rheum. 2002;  46 1820-1829
• 105 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
• 106 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
• 107 Andus T, Klebl F, Rogler G et al.. Patients with refractory Crohn's disease or ulcerative colitis respond to dehydroepiandrosterone: a pilot study.  Aliment Pharmacol Ther. 2003;  17 409-414
• 108 Oelkers W. Dehydroepiandrosterone for adrenal insufficiency.  N Engl J Med. 1999;  341 1073-1074
• 109 Achermann J C, Silverman B L. Dehydroepiandrosterone replacement for patients with adrenal insufficiency.  Lancet. 2001;  357 1381-1382