DHEA, 17α-AED, 17β-AED, and 17β-AET exhibit strong biological activity that has been attributed to androgenic, estrogenic, or antiglucocorticoid activity in vivo and in vitro. This study compared DHEA, 17α-AED, 17β-AED, and 17β-AET for their ability to activate the human AR, ER, and GR and determine the relative androgenicity, estrogenicity, and glucocorticoid activity. The results show that, at the receptor level, these androstene hormones are weak AR and even weaker ER activators. Direct androstene hormone activation of the human AR, ERα, and ERβ may not be essential for their biological function. Similarly, these hormones indirectly activated the human GR, only in the presence of high dexamethasone concentrations. These results underscore the major difference between androstene hormone interactions with these nuclear receptors and their biological effects. 1. Introduction DHEA, an androstene hormone, has been shown to possess a wide range of beneficial biological effects mainly attributed to immune system modulation [1]. DHEA is metabolized into more active metabolites, that is, 17β-AED and 17β-AET, as well as testosterone and estradiol [1, 2]. 17β-AED and 17β-AET have been reported to prevent the morbidity and mortality of otherwise lethal infections [3, 4], potentiate lymphocyte activation, and counteract the immune suppressive action of hydrocortisone [5–7], thus leading to beneficial effects in diverse human diseases including resistance to infection, neuroprotection, wound healing, diabetes, hepatic injury, cardiovascular disease, and cancer [8–10]. 17α-AED mediates autophagy of glial and breast cancers and apoptosis of myeloid tumor cells [11–13]. 17β-AED and 17α-AED naturally exist in epimeric forms based on whether the hydroxyl group is above (β) or below (α) the cycloperhydrophenanthrene ring. Addition of a hydroxyl group at the C7 position to 17β-AED results in the formation of -androstene-3β, 7β, 17β-triol (17β-AET). The biological activities of 17α-AED, 17β-AED, and 17β-AET have exhibited a structure-activity relationship that depends on the orientation and location of the hydroxyl groups [13]. Androstene hormones (AH) have been shown to promulgate their biological effects in many different animal models including mice, rats, monkeys, and some specific human tissues. Reports have associated the mechanism of action of androstene hormone metabolites with androgen, estrogen, and glucocorticoid receptor activity [14–16]. Adrenal hormones have been shown to activate both androgen and estrogen constructs. In this regard, it has been documented
References
[1]
J. S. Dillon, “Dehydroepiandrosterone, dehydroepiandrosterone sulfate and related steroids: their role in inflammatory, allergic and immunological disorders,” Current Drug Targets, vol. 4, no. 3, pp. 377–385, 2005.
[2]
R. Oberbeck and P. Kobbe, “DEhydroepiandrosterone (DHEA): a steroid with multiple effects. Is there any possible option in the treatment of critical illness?” Current Medicinal Chemistry, vol. 17, no. 11, pp. 1039–1047, 2010.
[3]
R. M. Loria and D. A. Padgett, “Androstenediol regulates systemic resistance against lethal infections in mice,” Annals of the New York Academy of Sciences, vol. 685, pp. 293–295, 1993.
[4]
R. M. Loria and D. A. Padgett, “Mobilization of cutaneous immunity for systemic protection against infections,” Annals of the New York Academy of Sciences, vol. 650, pp. 363–366, 1992.
[5]
R. M. Loria, D. A. Padgett, and P. N. Huynh, “Regulation of the immune response by dehydroepiandrosterone and its metabolites,” Journal of Endocrinology, vol. 150, pp. S209–S220, 1996.
[6]
R. M. Loria, “Antiglucocorticoid function of androstenetriol,” Psychoneuroendocrinology, vol. 22, supplement 1, pp. S103–S108, 1997.
[7]
D. A. Padgett, R. M. Loria, and J. F. Sheridan, “Endocrine regulation of the immune response to influenza virus infection with a metabolite of DHEA-androstenediol,” Journal of Neuroimmunology, vol. 78, no. 1-2, pp. 203–211, 1997.
[8]
F. Svec and J. R. Porter, “The actions of exogenous dehydroepiandrosterone in experimental animals and humans,” Proceedings of the Society for Experimental Biology and Medicine, vol. 218, no. 3, pp. 174–191, 1998.
[9]
C. D. Santos, M. P. A. Toldo, F. H. Santello, M. D. V. Filipin, V. Braz？o, and J. C. do Prado Júnior, “Dehydroepiandrosterone increases resistance to experimental infection by Trypanosoma cruzi,” Veterinary Parasitology, vol. 153, pp. 238–243, 2008.
[10]
V. R. Feeser, N. B. Menke, K. R. Ward, R. M. Loria, and R. F. Diegelmann, “Androstenediol reverses steroid-inhibited wound healing: biomedical hypothesis article,” Wound Repair and Regeneration, vol. 17, no. 5, pp. 758–761, 2009.
[11]
P. Huynh and R. Loria, “Contrasting effects of alpha- and beta-androstenediol on oncogenic myeloid cell lines in vitro,” Journal of Leukocyte Biology, vol. 62, no. 2, pp. 258–2267, 1997.
[12]
M. R. Graf, W. Jia, and R. M. Loria, “The neuro-steroid, 3β androstene 17α diol exhibits potent cytotoxic effects on human malignant glioma and lymphoma cells through different programmed cell death pathways,” British Journal of Cancer, vol. 97, no. 5, pp. 619–627, 2007.
[13]
M. R. Graf, W. Jia, M. L. Lewbart, and R. M. Loria, “The anti-tumor effects of androstene steroids exhibit a strict structure-activity relationship dependent upon the orientation of the hydroxyl group on carbon-17,” Chemical Biology and Drug Design, vol. 74, no. 6, pp. 625–629, 2009.
[14]
H. Miyamoto, S. Yeh, H. Lardy, E. Messing, and C. Chang, “δ5-Androstenediol is a natural hormone with androgenic activity in human prostate cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 19, pp. 11083–11088, 1998.
[15]
R. Hackenberg, I. Turgetto, A. Filmer, and K. D. Schulz, “Estrogen and androgen receptor mediated stimulation and inhibition of proliferation by androst-5-ene-3β,17β-diol in human mammary cancer cells,” Journal of Steroid Biochemistry and Molecular Biology, vol. 46, no. 5, pp. 597–603, 1993.
[16]
C. C. Head, M. J. Farrow, J. F. Sheridan, and D. A. Padgett, “Androstenediol reduces the anti-inflammatory effects of restraint stress during wound healing,” Brain, Behavior, and Immunity, vol. 20, no. 6, pp. 590–596, 2006.
[17]
P. Marwah, A. Marwah, H. A. Lardy, H. Miyamoto, and C. Chang, “C19-Steroids as androgen receptor modulators: design, discovery, and structure-activity relationship of new steroidal androgen receptor antagonists,” Bioorganic and Medicinal Chemistry, vol. 14, no. 17, pp. 5933–5947, 2006.
[18]
J. T. Arnold, X. Liu, J. D. Allen, H. Le, K. K. McFann, and M. R. Blackman, “Androgen receptor or estrogen receptor-β blockade alters DHEA-, DHT-, and E2-induced proliferation and PSA production in human prostate cancer cells,” Prostate, vol. 67, no. 11, pp. 1152–1162, 2007.
[19]
K. Saijo, J. G. Collier, A. C. Li, J. A. Katzenellenbogen, and C. K. Glass, “An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation,” Cell, vol. 145, no. 4, pp. 584–595, 2011.
[20]
D. A. Padgett and R. M. Loria, “In vitro potentiation of lymphocyte activation by dehydroepiandrosterone, androstenediol, and androstenetriol,” The Journal of Immunology, vol. 153, no. 4, pp. 1544–1552, 1994.
[21]
R. M. Loria and D. A. Padgett, “Androstenediol regulates systemic resistance against lethal infections in mice,” Archives of Virology, vol. 127, no. 1–4, pp. 103–115, 1992.
[22]
F. Chen, K. Knecht, E. Birzin et al., “Direct agonist/antagonist functions of dehydroepiandrosterone,” Endocrinology, vol. 146, no. 11, pp. 4568–4576, 2005.
[23]
M. E. Baker, “Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors,” Molecular and Cellular Endocrinology, vol. 215, no. 1-2, pp. 55–62, 2004.
[24]
R. M. Loria and M. R. Graf, “17α-androstenediol-mediated oncophagy of tumor cells by different mechanisms is determined by the target tumor,” Annals of the New York Academy of Sciences, vol. 1262, no. 1, pp. 127–133, 2012.
[25]
C. Honer, K. Nam, C. Fink et al., “Glucocorticoid receptor antagonism by cyproterone acetate and RU486,” Molecular Pharmacology, vol. 63, no. 5, pp. 1012–1020, 2003.
[26]
K. Matsumoto, H. Yamasaki, S. Akazawa et al., “High-dose but not low-dose dexamethasone impairs glucose tolerance by inducing compensatory failure of pancreatic β-cells in normal men,” Journal of Clinical Endocrinology and Metabolism, vol. 81, no. 7, pp. 2621–2626, 1996.
[27]
P. N. Huynh, W. H. Carter, and R. M. Loria, “17 Alpha androstenediol inhibition of breast tumor cell proliferation in estrogen receptor-positive and -negative cell lines,” Cancer Detection and Prevention, vol. 24, no. 5, pp. 435–444, 2000.
[28]
R. Loria, M. Graf, W. Jia, and T. Powell, “5-androstene 3β,17α diol induces autophagic cell death of human breast cancer cells and enhances radiation cytotoxicity,” Journal of Cancer Therapeutics and Research, vol. 1, no. 1, 25 pages, 2012.
