Advances in understanding the regulation and biologic actions of dehydroepiandrosterone

Current Opinion in Endocrinology and Diabetes

Volumn 3, Issue 3, 1996, Pages 202-211

  Nestler, John E ^a  

^a VIRGINIA COMMONWEALTH UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 0000940715     PISSN: 10683097     EISSN: None     Source Type: Journal    
DOI: 10.1097/00060793-199606000-00003     Document Type: Article

References (75)

1. Bellino FL, Daynes RA, Hornsby PJ, Lavrin DH, Nestler JE: Dehydroepiandrosterone (DHEA) and aging. Ann N Y Acad Sci 1995, 774:1-351. This volume is the published proceedings of the international conference on Dehydroepiandrosterone (DHEA) and Aging, sponsored by the New York Academy of Sciences in Washington, DC, from June 17 to 19, 1995. As such, it is an excellent compendium of past and current research in the area.
2. Thomas G, Frenoy N, Legrain S, Sebag-Lanoe R, Baulieu EE, Debuire B: Serum dehydroepiandrosterone sulfate levels as an individual marker. J Clin Endocrinol Metab 1994, 79:1273-1276.
3. Barrett-Connor E, Khaw KT, Yen SSC: A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease. N Engl J Med 1986, 315:1519-1524.
4. Orentreich N, Brind JL, Vogelman JH, Andres R, Baldwin H: Long-term longitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men. J Endocrinol Metab 1992, 75:1002-1004. This is the first longitudinal study of dehydroepiandrosterone sulfate levels in men. Although it confirms the findings of previous cross-sectional studies that there exists an age-related decline in levels of serum dehydroepiandrosterone sulfate, it also shows that in a subset of men serum dehydroepiandrosterone sulfate may actually rise with aging I This surprising finding has important implicatons for the regulation of dehydroepiandrosterone sulfate metabolism.
5. Zumoff B, Rosenfeld RS, Strain GW, Levin J, Fukushima DK: Sex differences in the twenty-four-hour mean plasma concentrations of dehydroepiandrosterone (DHA) and dehydroepiandrosterone sulfate (DHAS) and the DHA to DHAS ratio In normal adults. J Clin Endocrinol Metab 1980, 51:330-333.
6. Zumoff B, Bradlow HL: Sex differences in the metabolism of dehydroepiandrosterone sulfate. J Clin Endocrinol Metab 1980, 51:334-336.
7. Rice T, Sprecher DL, Borecki IB, Mitchell LE, Laskarzewski PM, Rao DC: The Cincinnati Myocardial Infarction and Hormone Family Study: family resemblance for dehydroepiandrosterone sulfate in control and myocardial infarction families. Metabolism 1993, 42:1284-1290. This genetic study shows that serum dehydroepiandrosterone sulfate levels in women are controlled primarily by heritable factors, whereas in men heredity seems to play only a minor role. These findings add substantial support to the idea that significant sex-based differences exist in the regulation of serum dehydroepiandrosterone sulfate concentrations.
8. Polderman KH, Gorren LJG, van der Veen EA: Effects of gonadal androgens and oestrogens on adrenal androgen levels. Clin Endocrinol (Oxf) 1995, 43:415-421.
9. Liu CH, Laughlin GA, Fischer UG, Yen SSC: 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.
10. Schiebinger RJ, Albertson BD, Cassorla FG, Bowyer DW, Geelhoed GW, Cutler GB Jr, Loriaux DL: The developmental changes In plasma adrenal androgens during infancy and adrenarche are associated with changing activities of adrenal microsomal 17-hydroxylase and 17,20-desmolase. J Clin Invest 1981, 67:1177-1182.
11. Penhoat A, Sanchez P, Jaillard C, Langlois D, Begeot M, Saez JM: Human proopiomelanocortin-(79-96), a proposed cortical androgen-stimulating hormone, does not affect steroidogenesis in cultured human adult adrenal cells. J Clin Endocrinol Metab 1991, 72:23-26.
12. Mellon SH, Shively JE, Miller WL: Human proopiomelanocortin-(79-96), a proposed androgen stimulatory hormone, does not affect steroidogenesis in cultured human fetal adrenal cells. J Clin Endocrinol Metab 1991, 72:19-22.
13. Nestler JE, Usiskin KS, Barlascini CO, Welty DF, Clore JN, Blackard WG: Suppression of serum dehydroepiandrosterone sulfate levels by insulin: an evaluation of possible mechanisms. J Clin Endocrinol Metab 1989, 69:1040-1046.
14. Nestler JE, McClanahan MA, Clore JN, Blackard WG: Insulin inhibits adrenal 17,20-lyase activity in men. J Clin Endocrinol Metab 1992, 74:362-367.
15. Nestler JE, Kahwash Z: Sex-specific action of insulin to acutely increase the metabolic clearance rate of dehydroepiandrosterone in humans. J Clin Invest 1994, 94:1484-1489. This paper demonstrates a significant sex-based difference in dehydroepiandrosterone metabolism between men and women. Insulin significantly increased the metabolic clearance rate for dehydroepiandrosterone in men by close to 50%, whereas no change in this parameter was observed in women studied identically.
16. Nestler JE, Beer NA, Jakubowicz DJ, Colombo C, Beer RM: Effects of insulin reduction with benfluorex on serum dehydroepiandrosterone (DHEA), DHEA-sulfate, and blood pressure in hypertensive middle-aged and elderly men. J Clin Endocrinol Metab 1995, 80:700-706. This study shows that the age-related decline in serum dehydroepiandrosterone and dehydroepiandrosterone sulfate levels in men is not inexorable but can be partially reversed. Specifically, it demonstrates a selective rise in serum levels of these steroids when insulin sensitivity and hyperinsulinemia are improved via the administration of benfluorex.
17. Nestler JE: Are there sex-specific effects of insulin on human dehydroepiandrosterone metabolism? Semin Reprod Endocrinol 1995, 13:282-287.
18. Shimokata H, Muller DC, Fleg JL, Sorkin J, Ziemba AW, Andres R: Age as independent determinant of glucose tolerance. Diabetes 1991, 40:44-51.
19. Lopez SA, Krehl WA: A possible interrelation between glucose-6-phosphate dehydrogenase and dehydroepiandrosterone in obesity. Lancet 1967, 2:485-487.
20. Nafziger AN, Herrington DM, Bush TL: Dehydroepiandrosterone and dehydroepiandrosterone sulfate: their relation to cardiovascular disease. Epidemiol Rev 1991, 13:267-293.
21. Barren-Connor E: Lower endogenous androgen levels and dyslipidemia in men with non-insulin-dependent diabetes mellitus. Ann Intern Med 1992, 117:807-811.
22. Jakubowicz DJ, Beer NA, Beer RM, Nestler JE: Disparate effects of weight reduction by diet on serum dehydroepiandrosterone-sulfate levels in obese men and women. J Clin Endocrinol Metab 1995, 80:3373-3376.
23. Cunningham SK, McKenna TJ: Dissociation of adrenal androgen and cortisol secretion in Cushing's syndrome. Clin Endocrinol (Oxf) 1994, 41:795-800. This paper shows that serum dehydroepiandrosterone sulfate levels are usually normal in individuals with Cushing's syndrome, again demonstrating a dissociation between adrenal androgen and cortisol secretion in some pathologic conditions. The implication is that a factor or factors other than corticotropin must regulate adrenal dehydroepiandrosterone and dehydroepiandrosterone sulfate production.
24. Gonzalez-Hernandez JA, Bornstein SR, Ehrhart-Bornstein M, Spath-Schwalbe E, Jirikowski G, Scherbaum WA: Interleukin-6 messenger ribonucleic acid expression in human adrenal gland in vivo: new clue to a paracrine or autocrine regulation of adrenal function. J Clin Endocrinol Metab 1994, 79:1492-1497.
25. Stankovic AK, Dion LD, Parker CR Jr: Effects of transforming growth factor-beta on human fetal adrenal steroid production. Mol Cell Endocrinol 1994, 99:145-151.
26. Kask E: 17-Ketosteroids and arteriosclerosis. Angiology 1959, 10:358-366.
27. Slowinska-Srzednicka J, Zgliczynski S, Ciswicka-Sznajderman M, Srzednicki M, Soszynski P, Biernacka M, Woroszylska M, Ruzyllo W, Sadowski Z: Decreased plasma dehydroepiandrosterone sulfate and dihydrotestosterone concentrations in young men after myocardial infarction. Atherosclerosis 1989, 79:197-203.
28. Mitchell LE, Sprecher DL, Borecki IB, Rice T, Laskarzewski PM, Rao DC: Evidence for an association between dehydroepiandrosterone sulfate and nonfatal, premature myocardial infarction in males. Circulation 1994, 89:89-93.
29. Barrett-Connor E, Goodman-Gruen D: The epidemiology of DHEAS and cardiovascular disease. Ann N Y Acad Sci 1995, 774:259-270.
30. Herrington DM, Gordon GB, Achuff SC, Trejo JF, Weisman HF, Kwiterovich PO, Pearson TA: Plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate in patients undergoing diagnostic coronary angiography. J Am Coll Cardiol 1990, 16:862-870.
31. Ishihara F, Hiramatsu K, Shigematsu S, Aizawa T, Niwa A, Takasu N, Yamada T, Matsuo K: Role of adrenal androgens in the development of arteriosclerosis as judged by pulse wave velocity and calcification of the aorta. Cardiology 1992, 80:332-338.
32. Coleman MP, Key TJ, Wang DY, Hermon C, Fentiman IS, Allen DS, Jarvis M, Pike MC, Sanders TA: A prospective study of obesity, lipids, apolipoproteins and ischaemic heart disease in women. Atherosclerosis 1992, 92:177-185.
33. Fassati P, Fassati M, Sonka J, Lesensky K: Dehydroepiandrosterone sulphate: a new approach to some cases of angina pectoris therapy. Aggressologie 1970, 11:421-426.
34. Gordon GB, Newitt JA, Shantz LM, Weng DE, Talalay P: Inhibition of the conversion of 3T3 fibroblast clones to adipocytes by dehydroepiandrosterone and related anticarcinogenic steroids. Cancer Res 1986, 46:3389-3395.
35. Ben-David M, Dikstein S, Bismuth G, Sulman FG: Anti-hypercholesterolemic effect of dehydroepiandrosterone in rats. Proc Soc Exp Biol Med 1967, 125:1136-1140.
36. Kurzman ID, MacEwen EG, Haffa ALM: Reduction In body weight and cholesterol in spontaneously obese dogs by dehydroepiandrosterone. Int J Obes 1990, 14:95-104.
37. Haffa AL, MacEwen EG, Kurzman ID, Kemnitz JW: Hypocholesterolemic effect of exogenous dehydroepiandrosterone administration in the rhesus monkey. In Vivo 1994, 8:993-997.
38. Nestler JE, Barlascini CO, Clore JN, Blackard WG: Dehydroepiandrosterone reduces serum low-density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men. J Clin Endocrinol Metab 1988, 66:57-61.
39. Jesse RL, Loesser K, Eich DM, Qian YZ, Hess ML, Nestler JE: Dehydroepiandrosterone inhibits human platelet aggregation in vitro and in vivo. Ann N Y Acad Scui 1995, 774:281-290.
40. Beer NA, Jakubowicz DJ, Malt DW, Beer RM, Nestler JE: Dehydroepiandrosterone reduces plasma plasminogen activator inhibitor type 1 and tissue plasminogen activator antigen in men. Am J Med Sci 1996, 311:205-210.
41. Hata T, Senoh D, Hata K, Kitao M, Masumura S: Effect of dehydroepiandrosterone sulfate on uterine artery flow velocity waveforms in term pregnancy. Obstet Gynecol 1995, 85:118-121. This paper demonstrates a vasodilatory effect of dehydroepiandrosterone on vascular blood flow. This finding has significant implications for dehydroepiandrosterone's putative cardioprotective actions. It also brings up the intriguing albeit highly speculative notion that dehydroepiandrosterone may influence endothelial nitric oxide releasel
42. Hata T, Hashimoto M, Senoh D, Hata K, Kitao M, Masumura S: Effect of dehydroepiandrosterone sulfate on ophthalmic artery flow velocity waveforms In full-term pregnant women. Am J Perinatol 1995, 12:135-137.
43. Meikle AW, Dorchuck RW, Araneo BA, Stringham JD, Evans TG, Spruance SL, Daynes RA: The presence of a dehydroepiandrosterone-specific receptor binding complex in murine T cells. J Steroid Biochem Mol Biol 1992, 42:293-304.
44. Okabe T, Haji M, Takayanagi R, Adachi M, Imasaki K, Kurimoto F, Watanabe T, Nawata H: Up-regulation of high-affinity dehydroepiandrosterone binding activity by dehydroepiandrosterone in activated human T lymphocytes. J Clin Endocrinol Metab 1995, 80:2993-2996. This is the first report of high-affinity binding of dehydroepiandrosterone to a human tissue. As such, it is an important communication. The finding is, however, controversial, as the binding was to stimulated cells only, and dehydroepiandrosterone did not elicit a biologic response.
45. Garg M, Bondada S: Reversal of age-associated decline in immune response to Pnu-imune vaccine by supplementation with the steroid hormone dehydroepiandrosterone. Infect Immun 1993, 61:2238-2241.
46. Padgett DA, Loria RM: In vitro potentiation of lymphocyte activation by dehydroepiandrosterone, androstenediol, and androstenetriol. J Immunol 1994, 153:1544-1552.
47. Suzuki T, Suzuki N, Daynes RA, Engleman EG: Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells. Clin Immunol Immunopathol 1991, 61:202-211.
48. Casson PR, Andersen RN, Herrod HG, Stentz FB, Straughn AB, Abraham GE, Buster JE: Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women. Am J Obstet Gynecol 1993, 169:1536-1539. This paper demonstrated, perhaps for the first time, modulation of immunologic parameters by dehydroepiandrosterone in postmenopausal women.
49. Yen SSC, Morales AJ, Khorram O: Replacement of DHEA in aging men and women. Ann N Y Acad Sci 1995, 774:128-142.
50. Van Vollenhoven RF, Engleman EG, McGuire JL: An open study of dehydroepiandrosterone in systemic lupus erythematosus. Arthritis Rheum 1994, 37:1305-1310. An important paper because it supports a therapeutic use for dehydroepiandrosterone in a human immunologic disorder. However, the study was uncontrolled, and a follow-up report from a properly controlled and randomized trial is eagerly awaited. The authors subsequently published a follow-up study of 28 women with systemic lupus erythematosus, this time using a double-blind, placebo-controlled study design (Arthritis Rheum 1995, 38:1826-1831). The results are most encouraging, and large-scale, chronic trials in patients with this disorder certainly seem warranted.
51. Parker CR Jr, Simpson ER, Bilheimer DW, Leveno K, Carr BR, MacDonald PC: Inverse relation between low-density lipoprotein-cholesterol and dehydroepiandrosterone sulfate in human fetal plasma. Science 1980, 208:512-514.
52. Lopez SA, Wingo C, Hebert JA: Total serum cholesterol and urinary dehydroepiandrosterone in humans. Atherosclerosis 1976, 24:471-481.
53. Nestler JE, Clore JN, Blackard WG: Dehydroepiandrosterone: the "missing link" between hyperinsulinemia and atherosclerosis? FASEB J 1992, 6:3073-3075.
54. Hellman L, Bradlow HL, Zumoff B, Fukushima DK, Gallagher TF: Thyroidandrogen interrelations and the hypocholesteremic effect of androsterone. J Clin Endocrinol Metab 1959, 19:936-948.
55. Felt V, Starka L: Metabolic effects of dehydroepiandrosterone and Atromid in patients with hyperlipaemia. Cor Vasa 1966, 8:40-48.
56. Nakagawa T, Ueyama Y, Nozaki S, Yamashita S, Menju M, Funahashi T, Kameda-Takemura K, Kubo M, Tokunaga K, Tanaka T: Marked hypocholesterolemia in a case with adrenal adenoma-enhanced catabolism of low density lipoprotein (LDL) via the LDL receptors of tumor cells. J Clin Endocrinol Metab 1995, 80:92-96. An interesting case report of highly elevated serum dehydroepiandrosterone and dehydroepiandrosterone sulfate associated with hypocholesterolemia in a girl with an adrenal adenoma. Serum dehydroepiandrosterone, dehydroepiandrosterone sulfate, and cholesterol levels returned to normal following removal of the tumor, suggesting a causal relationship. More recently, a letter to the editor described another similar case (Benvenga [J Clin Endocrinol Metab 1995, 80:3391-3392]).
57. Usiskin KS, Butterworth S, Clore JN, Arad Y, Ginsberg HN, Blackard WG, Nestler JE: Lack of effect of dehydroepiandrosterone in obese men. Int J Obes 1990, 14:457-463.
58. Mortola JF, Yen SSC: The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab 1990, 71:696-704.
59. Morales AJ, Nolan JJ, Nelson JC, Yen SSC: Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994, 78:1360-1367. An important paper because its results suggest that dehydroepiandrosterone replacement therapy may be worthwhile in elderly individuals. However, the results were less impressive than hoped for, with the main beneficial outcome being an improved sense of well being. Nonetheless, this group has conducted a follow-up study of greater duration and the findings are eagerly awaited.
60. Casson PR, Faquin LC, Stentz FB, Straughn AB, Andersen RN, Abraham GE, Buster JE: Replacement of dehydroepiandrosterone enhances T-lymphocyte insulin binding in postmenopausal women. Fertil Steril 1995, 63:1027-1031.
61. Svec F, Abadie J, Browne ES, Porter JR: Dehydroepiandrosterone and macronutrient selection by obese Zucker rats (fa/fa). Appetite 1995, 25:143-154. Dehydroepiandrosterone may be an antiobesity agent, although studies in human beings have been sparse and disappointing. Nonetheless, if dehydroepiandrosterone does act to reduce weight, could one mechanism be modulation of preference for fat versus protein versus carbohydrate? The findings of this interesting study suggest the answer is yes.
62. Abrahamsson L, Hackl H: Catabolic effects and the influence of hormonal variables under treatment with Gynodian-Depot or dehydroepiandrosterone (DHEA) oenanthate. Maturitas 1981, 3:225-234.
63. Welle S, Jozefowicz R, Statt M: Failure of dehydroepiandrosterone to infuence energy and protein metabolism in humans. J Clin Endocrinol Metab 1990, 71:1259-1264.
64. Zumoff B, Strain GW, Heymsfield SB, Lichtman S: A randomized double-blind crossover study of the antiobesity effects of etiocholanedione. Obes Res 1994, 2:13-18. Although the results of this study are not earth-shattering (average weight loss was only 2.8 kg), they are highly important because they provide support for the idea that dehydroepiandrosterone may possess antiobesity properties.
65. Buffington CK, Pourmotabbed G, Kitabchi AE: Case report: amelioration of insulin resistance in diabetes with dehydroepiandrosterone. Am J Med Sci 1993, 306:320-324.
66. 3H)DHEA binding in rat liver. Biochem Biophys Res Commun 1988, 156:22-29.
67. Mohan PF, Cleary MP: Studies on nuclear binding of dehydroepiandrosterone in hepatocytes. Steroids 1992, 57:244-247.
68. Yen TT, Allan JA, Pearson DV, Acton JM: Prevention of obesity in Avy/a mice by dehydroepiandrosterone. Lipids 1977, 12:409-413.
69. Bobyleva V, Kneer N, Bellei M, Battelli D, Lardy HA: Concerning the mechanism of increased thermogenesis In rats treated with dehydroepiandrosterone. J Bioenerg Biomembr 1993, 25:313-321.
70. Browne ES, Wright BE, Porter JR, Svec F: Dehydroepiandrosterone: antiglucocorticoid action in mice. Am J Med Sci 1992, 303:366-371.
71. Spivak CE: Desensitization and noncompetitive blockade in GABAA receptors in ventral midbrain neurons by a neurosterold dehydroepiandrosterone sulfate. Synapse 1994, 16:113-122.
72. Monnet FP, Mahe V, Robel P, Baulieu EE: Neurosteroids, via sigma receptors, modulate the <3H>norepinephrine release evoked by N-methyl-D-aspartate In the rat hippocampus. Proc Natl Acad Sci USA 1995, 92:3774-3778. Another report from this highly esteemed group demonstrating that dehydroepiandrosterone may function as a neuromodulator (ie, neurosteroid) via binding to central nervous system receptors. The question remains, however, whether this is pertinent to humans. Dehydroepiandrosterone biosynthesis in the central nervous system has been demonstrated in rats only and may not occur in human beings. On the other hand, circulating dehydroepiandrosterone does cross the blood-brain barrier and may interact with these central nervous system binding sites.
73. Lardy H, Partridge B, Kneer N, Wei Y: Ergosterolds: Induction of thermogenic enzymes In liver of rats treated with steroids derived from dehydroepiandrosterone. Proc Natl Acad Sci U S A 1995, 92:6617-6619. This report suggests that 7-oxygenated derivatives of dehydroepiandrosterone may be more potent than dehydroepiandrosterone in inducing thermogenic enzymes. Hence they may be more useful therapeutic agents for reducing obesity in humans.
74. Roy R, Bélanger A: ZR-75-1 breast cancer cells generate nonconjugated steroids from low density lipoprotein-incorporated lipoidal dehydroepiandrosterone. Endocrinology 1993, 133:683-689.
75. Lavallée B, Provost PR, Kahwash Z, Nestler JE, Bélanger A: Effect of insulin on plasma levels of DHEA metabolites In men [abstract]. Program of the New York Academy of Sciences conference on "Dehydroepiandrosterone (DHEA) and Aging," June 17-19, 1995. 1995:12.