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Dehydroepiandrosterone on metabolism and the cardiovascular system in the postmenopausal period

  • Caio Jordão Teixeira
  • Katherine Veras
  • Carla Roberta de Oliveira CarvalhoEmail author
Review

Abstract

Dehydroepiandrosterone (DHEA), mostly present as its sulfated ester (DHEA-S), is an anabolic hormone that naturally declines with age. Furthermore, it is the most abundant androgen and estrogen precursor in humans. Low plasma levels of DHEA have been strongly associated with obesity, insulin resistance, dyslipidemia, and high blood pressure, increasing the risk of cardiovascular disease. In this respect, DHEA could be regarded as a promising agent against metabolic syndrome (MetS) in postmenopausal women, since several age-related metabolic diseases are reported during aging. There are plenty of experimental evidences showing beneficial effects after DHEA therapy on carbohydrate and lipid metabolism, as well as cardiovascular health. However, its potential as a therapeutic agent appears to attract controversy, due to the lack of effects on some symptoms related to MetS. In this review, we examine the available literature regarding the impact of DHEA therapy on adiposity, glucose metabolism, and the cardiovascular system in the postmenopausal period. Both clinical studies and in vitro and in vivo experimental models were selected, and where possible, the main cellular mechanisms involved in DHEA therapy were discussed.

Schematic representation showing some of the general effects observed after administration DHEA therapy on target tissues of energy metabolism and the cardiovascular system. ↑ represents an increase, ↓ represents a decrease, – represents a worsening and ↔ represents no change after DHEA therapy

Keywords

Dehydroepiandrosterone Menopause Adiposity Insulin resistance Metabolic syndrome Cardiovascular disease 

Notes

Acknowledgments

The authors acknowledge Charles Serpellone Nash for his language revision.

Author contribution

CJT and KV wrote the main text, CROC suggested the idea and helped with the text, and CJT designed the figures. All authors have edited and approved the final version of the manuscript.

Funding information

This study was supported by grants from the Brazilian research agencies: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES-Finance Code 001), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP-2012/14183-7), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-303543/2014-0).

Compliance with Ethical Standards

Conflicts of interest

The authors declare that there is no conflict of interest.

References

  1. 1.
    Hallajzadeh J, Khoramdad M, Izadi N, Karamzad N, Almasi-Hashiani A, Ayubi E, Qorbani M, Pakzad R, Hasanzadeh A, Sullman MJM et al (2018) Metabolic syndrome and its components in premenopausal and postmenopausal women: a comprehensive systematic review and meta-analysis on observational studies. Menopause.  https://doi.org/10.1097/GME.0000000000001136 PubMedGoogle Scholar
  2. 2.
    Shook RP, Blair SN, Duperly J, Hand GA, Matsudo SM, Slavin JL (2014) What is causing the worldwide rise in body weight? Eur Endocrinol 10: 136-144. DOI 10.17925/EE.2014.10.02.136PubMedPubMedCentralGoogle Scholar
  3. 3.
    Wang X, Simpson ER, Brown KA (2015) Aromatase overexpression in dysfunctional adipose tissue links obesity to postmenopausal breast cancer. J Steroid Biochem Mol Biol 153:35–44PubMedGoogle Scholar
  4. 4.
    Santen RJ, Allred DC, Ardoin SP, Archer DF, Boyd N, Braunstein GD, Burger HG, Colditz GA, Davis SR, Gambacciani M et al (2010) Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 95:s1–s66PubMedPubMedCentralGoogle Scholar
  5. 5.
    Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, Manson JE, Stefanick ML, Ockene J, Sarto GE et al (2010) Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 304:1684–1692PubMedPubMedCentralGoogle Scholar
  6. 6.
    Laliberté F, Dea K, Duh MS, Kahler KH, Rolli M, Lefebvre P (2018) Does the route of administration for estrogen hormone therapy impact the risk of venous thromboembolism? Estradiol transdermal system versus oral estrogen-only hormone therapy. Menopause 25:1297–1305PubMedGoogle Scholar
  7. 7.
    Cushman M, Larson JC, Rosendaal FR, Heckbert SR, Curb JD, Phillips LS, Baird AE, Eaton CB, Stafford RS (2018) Biomarkers, menopausal hormone therapy and risk of venous thrombosis: the Women's Health Initiative. Res Pract Thromb Haemost 2:310–319PubMedPubMedCentralGoogle Scholar
  8. 8.
    Zhou Y, Kang J, Chen D, Han N, Ma H (2015) Ample evidence: dehydroepiandrosterone (DHEA) conversion into activated steroid hormones occurs in adrenal and ovary in female rat. PLoS One 10:e0124511.  https://doi.org/10.1371/journal.pone.0124511 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Grasfeder LL, Gaillard S, Hammes SR, Ilkayeva O, Newgard CB, Hochberg RB, Dwyer MA, Chang CY, McDonnell DP (2009) Fasting-induced hepatic production of DHEA is regulated by PGC-1alpha, ERRalpha, and HNF4alpha. Mol Endocrinol 23:1171–1182PubMedPubMedCentralGoogle Scholar
  10. 10.
    Orentreich N, Brind JL, Rizer RL, Vogelman JH (1984) Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 59:551–555PubMedGoogle Scholar
  11. 11.
    Rainey WE, Carr BR, Sasano H, Suzuki T, Mason JI (2002) Dissecting human adrenal androgen production. Trends Endocrinol Metab 13:234–239PubMedGoogle Scholar
  12. 12.
    Brahimaj A, Muka T, Kavousi M, Laven JS, Dehghan A, Franco OH (2017) Serum dehydroepiandrosterone levels are associated with lower risk of type 2 diabetes: the Rotterdam study. Diabetologia 60:98–106PubMedGoogle Scholar
  13. 13.
    Herrington DM, Gordon GB, Achuff SC, Trejo JF, Weisman HF, Kwiterovich PO, Pearson TA (1990) Plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate in patients undergoing diagnostic coronary angiography. J Am Coll Cardiol 16:862–870PubMedGoogle Scholar
  14. 14.
    Yamaguchi Y, Tanaka S, Yamakawa T, Kimura M, Ukawa K, Yamada Y, Ishihara M, Sekihara H (1998) Reduced serum dehydroepiandrosterone levels in diabetic patients with hyperinsulinaemia. Clin Endocrinol 49:377–383Google Scholar
  15. 15.
    Villareal DT, Holloszy JO (2004) Effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial. JAMA 292:2243–2248PubMedGoogle Scholar
  16. 16.
    Weiss EP, Villareal DT, Fontana L, Han DH, Holloszy JO (2011) Dehydroepiandrosterone (DHEA) replacement decreases insulin resistance and lowers inflammatory cytokines in aging humans. Aging (Albany NY) 3: 533-542. DOI  https://doi.org/10.18632/aging.100327 PubMedPubMedCentralGoogle Scholar
  17. 17.
    Sato K, Iemitsu M (2018) The role of dehydroepiandrosterone (DHEA) in skeletal muscle. Vitam Horm 108:205–221PubMedGoogle Scholar
  18. 18.
    Veras K, Almeida FN, Nachbar RT, de Jesus DS, Camporez JP, Carpinelli AR, Goedecke JH, de Oliveira Carvalho CR (2014) DHEA supplementation in ovariectomized rats reduces impaired glucose-stimulated insulin secretion induced by a high-fat diet. FEBS Open Bio 4:141–146PubMedPubMedCentralGoogle Scholar
  19. 19.
    Kang J, Ge C, Yu L, Li L, Ma H (2016) Long-term administration of dehydroepiandrosterone accelerates glucose catabolism via activation of PI3K/Akt-PFK-2 signaling pathway in rats fed a high-fat diet. PLoS One 11:e0159077.  https://doi.org/10.1371/journal.pone.0159077 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Campbell CS, Caperuto LC, Hirata AE, Araujo EP, Velloso LA, Saad MJ, Carvalho CR (2004) The phosphatidylinositol/AKT/atypical PKC pathway is involved in the improved insulin sensitivity by DHEA in muscle and liver of rats in vivo. Life Sci 76:57–70PubMedGoogle Scholar
  21. 21.
    Sánchez J, Pérez-Heredia F, Priego T, Portillo MP, Zamora S, Garaulet M, Palou A (2008) Dehydroepiandrosterone prevents age-associated alterations, increasing insulin sensitivity. J Nutr Biochem 19:809–818PubMedGoogle Scholar
  22. 22.
    Yin FJ, Kang J, Han NN, Ma HT (2015) Effect of dehydroepiandrosterone treatment on hormone levels and antioxidant parameters in aged rats. Genet Mol Res 14:11300–11311PubMedGoogle Scholar
  23. 23.
    Jacob MH, Janner DR, Jahn MP, Kucharski LC, Belló-Klein A, Ribeiro MF (2009) DHEA effects on myocardial Akt signaling modulation and oxidative stress changes in aged rats. Steroids 74:1045–1050PubMedGoogle Scholar
  24. 24.
    Camporez JP, Akamine EH, Davel AP, Franci CR, Rossoni LV, Carvalho CR (2011) Dehydroepiandrosterone protects against oxidative stress-induced endothelial dysfunction in ovariectomized rats. J Physiol 589:2585–2596PubMedPubMedCentralGoogle Scholar
  25. 25.
    Cheng HH, Hu XJ, Ruan QR (2009) Dehydroepiandrosterone anti-atherogenesis effect is not via its conversion to estrogen. Acta Pharmacol Sin 30:42–53PubMedGoogle Scholar
  26. 26.
    Gómez-Santos C, Hernández-Morante JJ, Tébar FJ, Granero E, Garaulet M (2012) Differential effect of oral dehydroepiandrosterone-sulphate on metabolic syndrome features in pre- and postmenopausal obese women. Clin Endocrinol 77:548–554Google Scholar
  27. 27.
    Bhuiyan MS, Fukunaga K (2009) Stimulation of sigma-1 receptor signaling by dehydroepiandrosterone ameliorates pressure overload-induced hypertrophy and dysfunctions in ovariectomized rats. Expert Opin Ther Targets 13:1253–1265PubMedGoogle Scholar
  28. 28.
    Teixeira CJ, Ribeiro LM, Veras K, da Cunha Araujo LC, Curi R, de Oliveira Carvalho CR (2018) Dehydroepiandrosterone supplementation is not beneficial in the late postmenopausal period in diet-induced obese rats. Life Sci 202:110–116PubMedGoogle Scholar
  29. 29.
    Mortola JF, Yen SS (1990) The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J Clin Endocrinol Metab 71:696–704PubMedGoogle Scholar
  30. 30.
    Emer E, Yildiz O, Seyrek M, Demirkol S, Topal T, Kurt B, Sayal A (2016) High-dose testosterone and dehydroepiandrosterone induce cardiotoxicity in rats: assessment of echocardiographic, morphologic, and oxidative stress parameters. Hum Exp Toxicol 35:562–572PubMedGoogle Scholar
  31. 31.
    Panjari M, Bell RJ, Jane F, Adams J, Morrow C, Davis SR (2009) The safety of 52 weeks of oral DHEA therapy for postmenopausal women. Maturitas 63:240–245PubMedGoogle Scholar
  32. 32.
    Ng MK, Nakhla S, Baoutina A, Jessup W, Handelsman DJ, Celermajer DS (2003) Dehydroepiandrosterone, an adrenal androgen, increases human foam cell formation: a potentially pro-atherogenic effect. J Am Coll Cardiol 42:1967–1974PubMedGoogle Scholar
  33. 33.
    Klair JS, Yang JD, Abdelmalek MF, Guy CD, Gill RM, Yates K, Unalp-Arida A, Lavine JE, Clark JM, Diehl AM et al (2016) A longer duration of estrogen deficiency increases fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. Hepatology 64:85–91PubMedPubMedCentralGoogle Scholar
  34. 34.
    Côté I, Chapados NA, Lavoie JM (2014) Impaired VLDL assembly: a novel mechanism contributing to hepatic lipid accumulation following ovariectomy and high-fat/high-cholesterol diets? Br J Nutr 112:1592–1600PubMedGoogle Scholar
  35. 35.
    Van Sinderen ML, Steinberg GR, Jørgensen SB, Honeyman J, Chow JD, Herridge KA, Winship AL, Dimitriadis E, Jones ME, Simpson ER et al (2015) Effects of estrogens on adipokines and glucose homeostasis in female aromatase knockout mice. PLoS One 10:e0136143.  https://doi.org/10.1371/journal.pone.0136143 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Prough RA, Clark BJ, Klinge CM (2016) Novel mechanisms for DHEA action. J Mol Endocrinol 56:R139–R155PubMedGoogle Scholar
  37. 37.
    Karbowska J, Kochan Z (2013) Effects of DHEA on metabolic and endocrine functions of adipose tissue. Horm Mol Biol Clin Invest 14:65–74Google Scholar
  38. 38.
    McNelis JC, Manolopoulos KN, Gathercole LL, Bujalska IJ, Stewart PM, Tomlinson JW, Arlt W (2013) Dehydroepiandrosterone exerts antiglucocorticoid action on human preadipocyte proliferation, differentiation, and glucose uptake. Am J Physiol Endocrinol Metab 305:E1134–E1144PubMedPubMedCentralGoogle Scholar
  39. 39.
    Tchernof A, Labrie F (2004) Dehydroepiandrosterone, obesity and cardiovascular disease risk: a review of human studies. Eur J Endocrinol 151:1–14PubMedGoogle Scholar
  40. 40.
    De Pergola G, Zamboni M, Sciaraffia M, Turcato E, Pannacciulli N, Armellini F, Giorgino F, Perrini S, Bosello O, Giorgino R (1996) Body fat accumulation is possibly responsible for lower dehydroepiandrosterone circulating levels in premenopausal obese women. Int J Obes Relat Metab Disord 20:1105–1110PubMedGoogle Scholar
  41. 41.
    Nair KS, Rizza RA, O'Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R et al (2006) DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 355:1647–1659PubMedGoogle Scholar
  42. 42.
    Jankowski CM, Gozansky WS, Van Pelt RE, Wolfe P, Schwartz RS, Kohrt WM (2011) Oral dehydroepiandrosterone replacement in older adults: effects on central adiposity, glucose metabolism and blood lipids. Clin Endocrinol 75:456–463Google Scholar
  43. 43.
    Nestler JE, Barlascini CO, Clore JN, Blackard WG (1988) Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men. J Clin Endocrinol Metab 66:57–61PubMedGoogle Scholar
  44. 44.
    Han DH, Hansen PA, Chen MM, Holloszy JO (1998) DHEA treatment reduces fat accumulation and protects against insulin resistance in male rats. J Gerontol A Biol Sci Med Sci 53:B19–B24PubMedGoogle Scholar
  45. 45.
    Karbowska J, Kochan Z (2012) Fat-reducing effects of dehydroepiandrosterone involve upregulation of ATGL and HSL expression, and stimulation of lipolysis in adipose tissue. Steroids 77:1359–1365PubMedGoogle Scholar
  46. 46.
    Hakkak R, Bell A, Korourian S (2017) Dehydroepiandrosterone (DHEA) feeding protects liver steatosis in obese breast cancer rat model. Sci Pharm 85.  https://doi.org/10.3390/scipharm85010013 PubMedCentralGoogle Scholar
  47. 47.
    Hansen PA, Han DH, Nolte LA, Chen M, Holloszy JO (1997) DHEA protects against visceral obesity and muscle insulin resistance in rats fed a high-fat diet. Am J Phys 273:R1704–R1708Google Scholar
  48. 48.
    Fujioka K, Kajita K, Wu Z, Hanamoto T, Ikeda T, Mori I, Okada H, Yamauchi M, Uno Y, Morita H et al (2012) Dehydroepiandrosterone reduces preadipocyte proliferation via androgen receptor. Am J Physiol Endocrinol Metab 302:E694–E704PubMedGoogle Scholar
  49. 49.
    Tagliaferro AR, Ronan AM, Payne J, Meeker LD, Tse S (1995) Increased lipolysis to beta-adrenergic stimulation after dehydroepiandrosterone treatment in rats. Am J Phys 268:R1374–R1380Google Scholar
  50. 50.
    de Heredia FP, Cerezo D, Zamora S, Garaulet M (2007) Effect of dehydroepiandrosterone on protein and fat digestibility, body protein and muscular composition in high-fat-diet-fed old rats. Br J Nutr 97:464–470PubMedGoogle Scholar
  51. 51.
    Rice SP, Zhang L, Grennan-Jones F, Agarwal N, Lewis MD, Rees DA, Ludgate M (2010) Dehydroepiandrosterone (DHEA) treatment in vitro inhibits adipogenesis in human omental but not subcutaneous adipose tissue. Mol Cell Endocrinol 320:51–57PubMedGoogle Scholar
  52. 52.
    Lea-Currie YR, Wen P, McIntosh MK (1998) Dehydroepiandrosterone reduces proliferation and differentiation of 3T3-L1 preadipocytes. Biochem Biophys Res Commun 248:497–504PubMedGoogle Scholar
  53. 53.
    Yamada J, Sakuma M, Ikeda T, Fukuda K, Suga T (1991) Characteristics of dehydroepiandrosterone as a peroxisome proliferator. Biochim Biophys Acta 1092:233–243PubMedGoogle Scholar
  54. 54.
    Karbowska J, Kochan Z (2005) Effect of DHEA on endocrine functions of adipose tissue, the involvement of PPAR gamma. Biochem Pharmacol 70:249–257PubMedGoogle Scholar
  55. 55.
    Kajita K, Ishizuka T, Mune T, Miura A, Ishizawa M, Kanoh Y, Kawai Y, Natsume Y, Yasuda K (2003) Dehydroepiandrosterone down-regulates the expression of peroxisome proliferator-activated receptor gamma in adipocytes. Endocrinology 144:253–259PubMedGoogle Scholar
  56. 56.
    Legeza B, Marcolongo P, Gamberucci A, Varga V, Bánhegyi G, Benedetti A, Odermatt A (2017) Fructose, glucocorticoids and adipose tissue: implications for the metabolic syndrome. Nutrients 9.  https://doi.org/10.3390/nu9050426 PubMedCentralGoogle Scholar
  57. 57.
    Apostolova G, Schweizer RA, Balazs Z, Kostadinova RM, Odermatt A (2005) Dehydroepiandrosterone inhibits the amplification of glucocorticoid action in adipose tissue. Am J Physiol Endocrinol Metab 288:E957–E964PubMedGoogle Scholar
  58. 58.
    Tagawa N, Minamitani E, Yamaguchi Y, Kobayashi Y (2011) Alternative mechanism for anti-obesity effect of dehydroepiandrosterone: possible contribution of 11β-hydroxysteroid dehydrogenase type 1 inhibition in rodent adipose tissue. Steroids 76:1546–1553PubMedGoogle Scholar
  59. 59.
    Abadie JM, Wright B, Correa G, Browne ES, Porter JR, Svec F (1993) Effect of dehydroepiandrosterone on neurotransmitter levels and appetite regulation of the obese Zucker rat. The Obesity Research Program Diabetes. Diabetes 42:662–669PubMedGoogle Scholar
  60. 60.
    Porter JR, Abadie JM, Wright BE, Browne ES, Svec F (1995) The effect of discontinuing dehydroepiandrosterone supplementation on Zucker rat food intake and hypothalamic neurotransmitters. Int J Obes Relat Metab Disord 19:480–488PubMedGoogle Scholar
  61. 61.
    Wright BE, Svec F, Porter JR (1995) Central effects of dehydroepiandrosterone in Zucker rats. Int J Obes Relat Metab Disord 19:887–892PubMedGoogle Scholar
  62. 62.
    Svec F, Porter J (1997) The effect of dehydroepiandrosterone (DHEA) on Zucker rat food selection and hypothalamic neurotransmitters. Psychoneuroendocrinology 22(Suppl 1):S57–S62PubMedGoogle Scholar
  63. 63.
    Porter J, Van Vrancken M, Corll C, Thompson H, Svec F (2005) The influence of dehydroepiandrosterone and 8-OH-DPAT on the caloric intake and hypothalamic neurotransmitters of lean and obese Zucker rats. Am J Phys Regul Integr Comp Phys 288:R928–R935Google Scholar
  64. 64.
    Baulieu EE (1991) Neurosteroids: a new function in the brain. Biol Cell 71:3–10PubMedGoogle Scholar
  65. 65.
    Beaujean D, Do-Rego JL, Galas L, Mensah-Nyagan AG, Fredriksson R, Larhammar D, Fournier A, Luu-The V, Pelletier G, Vaudry H (2002) Neuropeptide Y inhibits the biosynthesis of sulfated neurosteroids in the hypothalamus through activation of Y(1) receptors. Endocrinology 143:1950–1963PubMedGoogle Scholar
  66. 66.
    Navar D, Saulis D, Corll C, Svec F, Porter JR (2006) Dehydroepiandrosterone (DHEA) blocks the increase in food intake caused by neuropeptide Y (NPY) in the Zucker rat. Nutr Neurosci 9:225–232PubMedGoogle Scholar
  67. 67.
    Wright BE, Browne ES, Svec F, Porter JR (1993) Divergent effect of dehydroepiandrosterone on energy intakes of Zucker rats. Physiol Behav 53:39–43PubMedGoogle Scholar
  68. 68.
    Catalina F, Kumar V, Milewich L, Bennett M (1999) Food restriction-like effects of dehydroepiandrosterone: decreased lymphocyte numbers and functions with increased apoptosis. Proc Soc Exp Biol Med 221:326–335PubMedGoogle Scholar
  69. 69.
    Weindruch R, McFeeters G, Walford RL (1984) Food intake reduction and immunologic alterations in mice fed dehydroepiandrosterone. Exp Gerontol 19:297–304PubMedGoogle Scholar
  70. 70.
    Catalina F, Speciale SG, Kumar V, Milewich L, Bennett M (2001) Food restriction-like effects of dietary dehydroepiandrosterone. Hypothalamic neurotransmitters and metabolites in male C57BL/6 and (C57BL/6 x DBA/2)F1 mice. Exp Biol Med (Maywood) 226:208–215Google Scholar
  71. 71.
    Chen YM, Lee HC, Chen MT, Huang CC, Chen WC (2018) Dehydroepiandrosterone supplementation combined with weight-loading whole-body vibration training (WWBV) affects exercise performance and muscle glycogen storage in middle-aged C57BL/6 mice. Int J Med Sci 15:564–573PubMedPubMedCentralGoogle Scholar
  72. 72.
    Ryu JW, Kim MS, Kim CH, Song KH, Park JY, Lee JD, Kim JB, Lee KU (2003) DHEA administration increases brown fat uncoupling protein 1 levels in obese OLETF rats. Biochem Biophys Res Commun 303:726–731PubMedGoogle Scholar
  73. 73.
    Tagliaferro AR, Davis JR, Truchon S, Van Hamont N (1986) Effects of dehydroepiandrosterone acetate on metabolism, body weight and composition of male and female rats. J Nutr 116:1977–1983PubMedGoogle Scholar
  74. 74.
    Gorres BK, Bomhoff GL, Gupte AA (1985) Geiger PC (2011) Altered estrogen receptor expression in skeletal muscle and adipose tissue of female rats fed a high-fat diet. J Appl Physiol 110:1046–1053Google Scholar
  75. 75.
    Safiulina D, Peet N, Seppet E, Zharkovsky A, Kaasik A (2006) Dehydroepiandrosterone inhibits complex I of the mitochondrial respiratory chain and is neurotoxic in vitro and in vivo at high concentrations. Toxicol Sci 93:348–356PubMedGoogle Scholar
  76. 76.
    Mayer D, Forstner K (2004) Impact of dehydroepiandrosterone on hepatocarcinogenesis in the rat (Review). Int J Oncol 25:1021–1030PubMedGoogle Scholar
  77. 77.
    Hotamisligil GS (2017) Inflammation, metaflammation and immunometabolic disorders. Nature 542:177–185PubMedGoogle Scholar
  78. 78.
    Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445PubMedGoogle Scholar
  79. 79.
    Sato K, Iemitsu M, Aizawa K, Ajisaka R (2009) DHEA improves impaired activation of Akt and PKC zeta/lambda-GLUT4 pathway in skeletal muscle and improves hyperglycaemia in streptozotocin-induced diabetes rats. Acta Physiol (Oxford) 197:217–225Google Scholar
  80. 80.
    Boura-Halfon S, Zick Y (2009) Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am J Physiol Endocrinol Metab 296:E581–E591PubMedGoogle Scholar
  81. 81.
    Araujo LCC, Feitosa KB, Murata GM, Furigo IC, Teixeira SA, Lucena CF, Ribeiro LM, Muscará MN, Costa SKP, Donato J et al (2018) Uncaria tomentosa improves insulin sensitivity and inflammation in experimental NAFLD. Sci Rep 8:11013PubMedPubMedCentralGoogle Scholar
  82. 82.
    Jacob MH, Janner DR, Araújo AS, Jahn MP, Kucharski LC, Moraes TB, Dutra Filho CS, Ribeiro MF, Belló-Klein A (2011) Dehydroepiandrosterone improves hepatic antioxidant reserve and stimulates Akt signaling in young and old rats. J Steroid Biochem Mol Biol 127:331–336PubMedGoogle Scholar
  83. 83.
    Aoki K, Tajima K, Taguri M, Terauchi Y (2016) Effect of dehydroepiandrosterone (DHEA) on Akt and protein kinase C zeta (PKCζ) phosphorylation in different tissues of C57BL6, insulin receptor substrate (IRS)1(-/-), and IRS2(-/-) male mice fed a high-fat diet. J Steroid Biochem Mol Biol 159:110–120PubMedGoogle Scholar
  84. 84.
    Cecconello AL, Trapp M, Hoefel AL, Marques CV, Arbo BD, Osterkamp G, Kucharski LC, Ribeiro MF (2015) Sex-related differences in the effects of high-fat diets on DHEA-treated rats. Endocrine 48:985–994PubMedGoogle Scholar
  85. 85.
    Jahn MP, Jacob MH, Gomes LF, Duarte R, Araújo AS, Belló-Klein A, Ribeiro MF, Kucharski LC (2010) The effect of long-term DHEA treatment on glucose metabolism, hydrogen peroxide and thioredoxin levels in the skeletal muscle of diabetic rats. J Steroid Biochem Mol Biol 120:38–44PubMedGoogle Scholar
  86. 86.
    Sato K, Iemitsu M, Aizawa K, Mesaki N, Ajisaka R, Fujita S (2012) DHEA administration and exercise training improves insulin resistance in obese rats. Nutr Metab (Lond) 9:47Google Scholar
  87. 87.
    Sato K, Iemitsu M, Aizawa K, Mesaki N, Fujita S (2011) Increased muscular dehydroepiandrosterone levels are associated with improved hyperglycemia in obese rats. Am J Physiol Endocrinol Metab 301:E274–E280PubMedGoogle Scholar
  88. 88.
    Ishizuka T, Kajita K, Miura A, Ishizawa M, Kanoh Y, Itaya S, Kimura M, Muto N, Mune T, Morita H et al (1999) DHEA improves glucose uptake via activations of protein kinase C and phosphatidylinositol 3-kinase. Am J Phys 276:E196–E204Google Scholar
  89. 89.
    Ishizuka T, Miura A, Kajita K, Matsumoto M, Sugiyama C, Matsubara K, Ikeda T, Mori I, Morita H, Uno Y et al (2007) Effect of dehydroepiandrosterone on insulin sensitivity in Otsuka Long-Evans Tokushima-fatty rats. Acta Diabetol 44:219–226PubMedGoogle Scholar
  90. 90.
    Kajita K, Ishizuka T, Miura A, Ishizawa M, Kanoh Y, Yasuda K (2000) The role of atypical and conventional PKC in dehydroepiandrosterone-induced glucose uptake and dexamethasone-induced insulin resistance. Biochem Biophys Res Commun 277:361–367PubMedGoogle Scholar
  91. 91.
    Perrini S, Natalicchio A, Laviola L, Belsanti G, Montrone C, Cignarelli A, Minielli V, Grano M, De Pergola G, Giorgino R et al (2004) Dehydroepiandrosterone stimulates glucose uptake in human and murine adipocytes by inducing GLUT1 and GLUT4 translocation to the plasma membrane. Diabetes 53:41–52PubMedGoogle Scholar
  92. 92.
    Hoefel AL, Arbo BD, Vieira-Marques C, Cecconello AL, Cozer AG, Ribeiro MFM, Kucharski LC (2018) Female rats are more susceptible to metabolic effects of dehydroepiandrosterone treatment. Can J Physiol Pharmacol:1–7.  https://doi.org/10.1139/cjpp-2018-0159 PubMedGoogle Scholar
  93. 93.
    Adeva-Andany MM, Pérez-Felpete N, Fernández-Fernández C, Donapetry-García C, Pazos-García C (2016) Liver glucose metabolism in humans. Biosci Rep 36.  https://doi.org/10.1042/BSR20160385
  94. 94.
    Chen WC, Chen YM, Huang CC, Tzeng YD (2016) Dehydroepiandrosterone supplementation combined with whole-body vibration training affects testosterone level and body composition in mice. Int J Med Sci 13:730–740PubMedPubMedCentralGoogle Scholar
  95. 95.
    Mayer D, Reuter S, Hoffmann H, Bocker T, Bannasch P (1996) Dehydroepiandrosterone reduces expression of glycolytic and gluconeogenic enzymes in the liver of male and female rats. Int J Oncol 8:1069–1078PubMedGoogle Scholar
  96. 96.
    Sato K, Iemitsu M, Aizawa K, Ajisaka R (2008) Testosterone and DHEA activate the glucose metabolism-related signaling pathway in skeletal muscle. Am J Physiol Endocrinol Metab 294:E961–E968PubMedGoogle Scholar
  97. 97.
    Greenberg CC, Jurczak MJ, Danos AM, Brady MJ (2006) Glycogen branches out: new perspectives on the role of glycogen metabolism in the integration of metabolic pathways. Am J Physiol Endocrinol Metab 291:E1–E8PubMedGoogle Scholar
  98. 98.
    Aoki K, Kikuchi T, Mukasa K, Ito S, Nakajima A, Satoh S, Okamura A, Sekihara H (2000) Dehydroepiandrosterone suppresses elevated hepatic glucose-6-phosphatase mRNA level in C57BL/KsJ-db/db mice: comparison with troglitazone. Endocr J 47:799–804PubMedGoogle Scholar
  99. 99.
    Aoki K, Saito T, Satoh S, Mukasa K, Kaneshiro M, Kawasaki S, Okamura A, Sekihara H (1999) Dehydroepiandrosterone suppresses the elevated hepatic glucose-6-phosphatase and fructose-1,6-bisphosphatase activities in C57BL/Ksj-db/db mice: comparison with troglitazone. Diabetes 48:1579–1585PubMedGoogle Scholar
  100. 100.
    Yamashita R, Saito T, Satoh S, Aoki K, Kaburagi Y, Sekihara H (2005) Effects of dehydroepiandrosterone on gluconeogenic enzymes and glucose uptake in human hepatoma cell line, HepG2. Endocr J 52:727–733PubMedGoogle Scholar
  101. 101.
    Aoki K, Taniguchi H, Ito Y, Satoh S, Nakamura S, Muramatsu K, Yamashita R, Ito S, Mori Y, Sekihara H (2004) Dehydroepiandrosterone decreases elevated hepatic glucose production in C57BL/KsJ-db/db mice. Life Sci 74:3075–3084PubMedGoogle Scholar
  102. 102.
    McIntosh MK, Berdanier CD (1991) Antiobesity effects of dehydroepiandrosterone are mediated by futile substrate cycling in hepatocytes of BHE/cdb rats. J Nutr 121:2037–2043PubMedGoogle Scholar
  103. 103.
    Dillon JS, Yaney GC, Zhou Y, Voilley N, Bowen S, Chipkin S, Bliss CR, Schultz V, Schuit FC, Prentki M et al (2000) Dehydroepiandrosterone sulfate and beta-cell function: enhanced glucose-induced insulin secretion and altered gene expression in rodent pancreatic beta-cells. Diabetes 49:2012–2020PubMedGoogle Scholar
  104. 104.
    Yue J, Wang L, Huang R, Li S, Ma J, Teng X, Liu W (2013) Dehydroepiandrosterone-sulfate (DHEAS) promotes MIN6 cells insulin secretion via inhibition of AMP-activated protein kinase. Biochem Biophys Res Commun 440:756–761PubMedGoogle Scholar
  105. 105.
    Almeida FN, Veras KM, Camporez JP, Felitti V, Chimin P, Carvalho CRO (2013) Dehydroepiandrosterone increases pancreatic duodenal homebox-1 (PDX-1) and reduces cleaved caspase-3 protein expression in insulin-secreting INS-1E cells. Research in Endocrinology. ENDO 2013:1–8Google Scholar
  106. 106.
    Ma J, Yue J, Huang R, Liao Y, Li S, Liu W (2018) Reversion of aging-related DHEAS decline in mouse plasma alleviates aging-related glucose tolerance impairment by potentiation of glucose-stimulated insulin secretion of acute phase. Biochem Biophys Res Commun 500:671–675PubMedGoogle Scholar
  107. 107.
    Giroix MH, Malaisse-Lagae F, Portha B, Sener A, Malaisse WJ (1997) Effects of dehydroepiandrosterone in rats injected with streptozotocin during the neonatal period. Biochem Mol Med 61:72–81PubMedGoogle Scholar
  108. 108.
    Coleman DL, Leiter EH, Schwizer RW (1982) Therapeutic effects of dehydroepiandrosterone (DHEA) in diabetic mice. Diabetes 31:830–833PubMedGoogle Scholar
  109. 109.
    Gansler TS, Muller S, Cleary MP (1985) Chronic administration of dehydroepiandrosterone reduces pancreatic beta-cell hyperplasia and hyperinsulinemia in genetically obese Zucker rats. Proc Soc Exp Biol Med 180:155–162PubMedGoogle Scholar
  110. 110.
    Medina MC, Souza LC, Caperuto LC, Anhê GF, Amanso AM, Teixeira VP, Bordin S, Carpinelli AR, Britto LR, Barbieri RL et al (2006) Dehydroepiandrosterone increases beta-cell mass and improves the glucose-induced insulin secretion by pancreatic islets from aged rats. FEBS Lett 580:285–290PubMedGoogle Scholar
  111. 111.
    Lasco A, Frisina N, Morabito N, Gaudio A, Morini E, Trifiletti A, Basile G, Nicita-Mauro V, Cucinotta D (2001) Metabolic effects of dehydroepiandrosterone replacement therapy in postmenopausal women. Eur J Endocrinol 145:457–461PubMedGoogle Scholar
  112. 112.
    Weiss EP, Villareal DT, Ehsani AA, Fontana L, Holloszy JO (2012) Dehydroepiandrosterone replacement therapy in older adults improves indices of arterial stiffness. Aging Cell 11:876–884PubMedPubMedCentralGoogle Scholar
  113. 113.
    Dhatariya K, Bigelow ML, Nair KS (2005) Effect of dehydroepiandrosterone replacement on insulin sensitivity and lipids in hypoadrenal women. Diabetes 54:765–769PubMedGoogle Scholar
  114. 114.
    Kimura M, Tanaka S, Yamada Y, Kiuchi Y, Yamakawa T, Sekihara H (1998) Dehydroepiandrosterone decreases serum tumor necrosis factor-alpha and restores insulin sensitivity: independent effect from secondary weight reduction in genetically obese Zucker fatty rats. Endocrinology 139:3249–3253PubMedGoogle Scholar
  115. 115.
    Liu D, Ren M, Bing X, Stotts C, Deorah S, Love-Homan L, Dillon JS (2006) Dehydroepiandrosterone inhibits intracellular calcium release in beta-cells by a plasma membrane-dependent mechanism. Steroids 71:691–699PubMedGoogle Scholar
  116. 116.
    Laychock SG, Bauer AL (1996) Epiandrosterone and dehydroepiandrosterone affect glucose oxidation and interleukin-1 beta effects in pancreatic islets. Endocrinology 137:3375–3385PubMedGoogle Scholar
  117. 117.
    Laychock SG (1998) Rat pancreatic islet and RINm5F cell responses to epiandrosterone, dehydroepiandrosterone and interleukin-1 beta. Biochem Pharmacol 55:1453–1464PubMedGoogle Scholar
  118. 118.
    Liu HK, Green BD, McClenaghan NH, McCluskey JT, Flatt PR (2006) Deleterious effects of supplementation with dehydroepiandrosterone sulphate or dexamethasone on rat insulin-secreting cells under in vitro culture condition. Biosci Rep 26:31–38PubMedGoogle Scholar
  119. 119.
    Rebelato E, Abdulkader F, Curi R, Carpinelli AR (2011) Control of the intracellular redox state by glucose participates in the insulin secretion mechanism. PLoS One 6:e24507.  https://doi.org/10.1371/journal.pone.0024507 CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Munhoz AC, Riva P, Simões D, Curi R, Carpinelli AR (2016) Control of Insulin Secretion by production of reactive oxygen species: study performed in pancreatic islets from fed and 48-hour fasted Wistar rats. PLoS One 11:e0158166.  https://doi.org/10.1371/journal.pone.0158166 CrossRefPubMedPubMedCentralGoogle Scholar
  121. 121.
    Spégel P, Sharoyko VV, Goehring I, Danielsson AP, Malmgren S, Nagorny CL, Andersson LE, Koeck T, Sharp GW, Straub SG et al (2013) Time-resolved metabolomics analysis of β-cells implicates the pentose phosphate pathway in the control of insulin release. Biochem J 450:595–605PubMedGoogle Scholar
  122. 122.
    Zhang Z, Liew CW, Handy DE, Zhang Y, Leopold JA, Hu J, Guo L, Kulkarni RN, Loscalzo J, Stanton RC (2010) High glucose inhibits glucose-6-phosphate dehydrogenase, leading to increased oxidative stress and beta-cell apoptosis. FASEB J 24:1497–1505PubMedPubMedCentralGoogle Scholar
  123. 123.
    Fang Z, Jiang C, Feng Y, Chen R, Lin X, Zhang Z, Han L, Chen X, Li H, Guo Y, et al. (2016) Effects of G6PD activity inhibition on the viability, ROS generation and mechanical properties of cervical cancer cells. Biochim Biophys Acta 1863: 2245-2254. DOI  https://doi.org/10.1016/j.bbamcr.2016.05.016 Google Scholar
  124. 124.
    Di Monaco M, Pizzini A, Gatto V, Leonardi L, Gallo M, Brignardello E, Boccuzzi G (1997) Role of glucose-6-phosphate dehydrogenase inhibition in the antiproliferative effects of dehydroepiandrosterone on human breast cancer cells. Br J Cancer 75:589–592PubMedPubMedCentralGoogle Scholar
  125. 125.
    Yoshida S, Honda A, Matsuzaki Y, Fukushima S, Tanaka N, Takagiwa A, Fujimoto Y, Miyazaki H, Salen G (2003) Anti-proliferative action of endogenous dehydroepiandrosterone metabolites on human cancer cell lines. Steroids 68:73–83PubMedGoogle Scholar
  126. 126.
    Zhao D, Guallar E, Ouyang P, Subramanya V, Vaidya D, Ndumele CE, Lima JA, Allison MA, Shah SJ, Bertoni AG et al (2018) Endogenous sex hormones and incident cardiovascular disease in post-menopausal women. J Am Coll Cardiol 71:2555–2566PubMedPubMedCentralGoogle Scholar
  127. 127.
    Labrie F, Labrie C (2013) DHEA and intracrinology at menopause, a positive choice for evolution of the human species. Climacteric 16:205–213PubMedGoogle Scholar
  128. 128.
    Davison SL, Bell R, Donath S, Montalto JG, Davis SR (2005) Androgen levels in adult females: changes with age, menopause, and oophorectomy. J Clin Endocrinol Metab 90:3847–3853PubMedGoogle Scholar
  129. 129.
    Subramanya V, Zhao D, Ouyang P, Lima JA, Vaidya D, Ndumele CE, Bluemke DA, Shah SJ, Guallar E, Nwabuo CC et al (2018) Sex hormone levels and change in left ventricular structure among men and post-menopausal women: the multi-ethnic study of atherosclerosis (MESA). Maturitas 108:37–44PubMedGoogle Scholar
  130. 130.
    Shufelt C, Bretsky P, Almeida CM, Johnson BD, Shaw LJ, Azziz R, Braunstein GD, Pepine CJ, Bittner V, Vido DA et al (2010) DHEA-S levels and cardiovascular disease mortality in postmenopausal women: results from the National Institutes of Health--National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE). J Clin Endocrinol Metab 95:4985–4992PubMedPubMedCentralGoogle Scholar
  131. 131.
    Jiménez MC, Sun Q, Schürks M, Chiuve S, Hu FB, Manson JE, Rexrode KM (2013) Low dehydroepiandrosterone sulfate is associated with increased risk of ischemic stroke among women. Stroke 44:1784–1789PubMedGoogle Scholar
  132. 132.
    Boxer RS, Kleppinger A, Brindisi J, Feinn R, Burleson JA, Kenny AM (2010) Effects of dehydroepiandrosterone (DHEA) on cardiovascular risk factors in older women with frailty characteristics. Age Ageing 39:451–458PubMedPubMedCentralGoogle Scholar
  133. 133.
    Cappola AR, Xue QL, Walston JD, Leng SX, Ferrucci L, Guralnik J, Fried LP (2006) DHEAS levels and mortality in disabled older women: the Women's Health and Aging Study I. J Gerontol A Biol Sci Med Sci 61:957–962PubMedPubMedCentralGoogle Scholar
  134. 134.
    Yoshida S, Aihara K, Azuma H, Uemoto R, Sumitomo-Ueda Y, Yagi S, Ikeda Y, Iwase T, Nishio S, Kawano H et al (2010) Dehydroepiandrosterone sulfate is inversely associated with sex-dependent diverse carotid atherosclerosis regardless of endothelial function. Atherosclerosis 212:310–315PubMedGoogle Scholar
  135. 135.
    Barrett-Connor E, Goodman-Gruen D (1995) Dehydroepiandrosterone sulfate does not predict cardiovascular death in postmenopausal women: The Rancho Bernardo Study. Circulation 91:1757–1760PubMedGoogle Scholar
  136. 136.
    Page JH, Ma J, Rexrode KM, Rifai N, Manson JE, Hankinson SE (2008) Plasma dehydroepiandrosterone and risk of myocardial infarction in women. Clin Chem 54:1190–1196PubMedPubMedCentralGoogle Scholar
  137. 137.
    Lizcano F, Guzmán G (2014) Estrogen deficiency and the origin of obesity during menopause. Biomed Res Int 2014: 757461. DOI  https://doi.org/10.1155/2014/757461 Google Scholar
  138. 138.
    Carr MC (2003) The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab 88:2404–2411PubMedGoogle Scholar
  139. 139.
    Stefanska A, Bergmann K, Sypniewska G (2015) Metabolic syndrome and menopause: pathophysiology, clinical and diagnostic significancE. Adv Clin Chem 72:1–75PubMedGoogle Scholar
  140. 140.
    Polotsky HN, Polotsky AJ (2010) Metabolic implications of menopause. Semin Reprod Med 28:426–434PubMedGoogle Scholar
  141. 141.
    Camilleri G, Borg M, Brincat S, Schembri-Wismayer P, Brincat M, Calleja-Agius J (2012) The role of cytokines in cardiovascular disease in menopause. Climacteric 15:524–530PubMedGoogle Scholar
  142. 142.
    Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B et al (2008) Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 117:e25-146PubMedGoogle Scholar
  143. 143.
    Lefebvre P, Chinetti G, Fruchart JC, Staels B (2006) Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 116:571–580PubMedPubMedCentralGoogle Scholar
  144. 144.
    Mascarenhas-Melo F, Sereno J, Teixeira-Lemos E, Ribeiro S, Rocha-Pereira P, Cotterill E, Teixeira F, Reis F (2013) Markers of increased cardiovascular risk in postmenopausal women: focus on oxidized-LDL and HDL subpopulations. Dis Markers 35:85–96PubMedPubMedCentralGoogle Scholar
  145. 145.
    Gill SK (2015) Cardiovascular risk factors and disease in women. Med Clin North Am 99:535–552PubMedGoogle Scholar
  146. 146.
    Hayashi T, Fukuto JM, Ignarro LJ, Chaudhuri G (1995) Gender differences in atherosclerosis: possible role of nitric oxide. J Cardiovasc Pharmacol 26:792–802PubMedGoogle Scholar
  147. 147.
    Sarrel PM (1999) Risks and benefits of hormone replacement therapy for the prevention of cardiovascular disease. Cardiologia 44(Suppl 1):515–518PubMedGoogle Scholar
  148. 148.
    Iorga A, Cunningham CM, Moazeni S, Ruffenach G, Umar S, Eghbali M (2017) The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy. Biol Sex Differ 8:33PubMedPubMedCentralGoogle Scholar
  149. 149.
    Anagnostis P, Paschou SA, Katsiki N, Krikidis D, Lambrinoudaki I, Goulis DG (2018) Menopausal hormone therapy and cardiovascular risk. Where are we now? Curr Vasc Pharmacol.  https://doi.org/10.2174/1570161116666180709095348 PubMedGoogle Scholar
  150. 150.
    Diamond P, Cusan L, Gomez JL, Bélanger A, Labrie F (1996) Metabolic effects of 12-month percutaneous dehydroepiandrosterone replacement therapy in postmenopausal women. J Endocrinol 150(Suppl):S43–S50PubMedGoogle Scholar
  151. 151.
    Casson PR, Santoro N, Elkind-Hirsch K, Carson SA, Hornsby PJ, Abraham G, Buster JE (1998) Postmenopausal dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density lipoprotein: a six-month trial. Fertil Steril 70:107–110PubMedGoogle Scholar
  152. 152.
    Borgo MV, Claudio ER, Silva FB, Romero WG, Gouvea SA, Moysés MR, Santos RL, Almeida SA, Podratz PL, Graceli JB et al (2016) Hormonal therapy with estradiol and drospirenone improves endothelium-dependent vasodilation in the coronary bed of ovariectomized spontaneously hypertensive rats. Braz J Med Biol Res 49:e4655.  https://doi.org/10.1590/1414-431X20154655 CrossRefPubMedGoogle Scholar
  153. 153.
    Wassmann S, Bäumer AT, Strehlow K, van Eickels M, Grohé C, Ahlbory K, Rösen R, Böhm M, Nickenig G (2001) Endothelial dysfunction and oxidative stress during estrogen deficiency in spontaneously hypertensive rats. Circulation 103:435–441PubMedGoogle Scholar
  154. 154.
    Cervellati C, Bergamini CM (2016) Oxidative damage and the pathogenesis of menopause related disturbances and diseases. Clin Chem Lab Med 54:739–753PubMedGoogle Scholar
  155. 155.
    Rangel-Zuñiga OA, Cruz-Teno C, Haro C, Quintana-Navarro GM, Camara-Martos F, Perez-Martinez P, Garcia-Rios A, Garaulet M, Tena-Sempere M, Lopez-Miranda J et al (2017) Differential menopause- versus aging-induced changes in oxidative stress and circadian rhythm gene markers. Mech Ageing Dev 164:41–48PubMedGoogle Scholar
  156. 156.
    Herrera MD, Mingorance C, Rodríguez-Rodríguez R, Alvarez de Sotomayor M (2010) Endothelial dysfunction and aging: an update. Ageing Res Rev 9:142–152PubMedGoogle Scholar
  157. 157.
    Eich DM, Nestler JE, Johnson DE, Dworkin GH, Ko D, Wechsler AS, Hess ML (1993) Inhibition of accelerated coronary atherosclerosis with dehydroepiandrosterone in the heterotopic rabbit model of cardiac transplantation. Circulation 87:261–269PubMedGoogle Scholar
  158. 158.
    Arad Y, Badimon JJ, Badimon L, Hembree WC, Ginsberg HN (1989) Dehydroepiandrosterone feeding prevents aortic fatty streak formation and cholesterol accumulation in cholesterol-fed rabbit. Arteriosclerosis 9:159–166PubMedGoogle Scholar
  159. 159.
    Gordon GB, Bush DE, Weisman HF (1988) Reduction of atherosclerosis by administration of dehydroepiandrosterone. A study in the hypercholesterolemic New Zealand white rabbit with aortic intimal injury J Clin Invest 82:712–720PubMedGoogle Scholar
  160. 160.
    Wang L, Hao Q, Wang YD, Wang WJ, Li DJ (2011) Protective effects of dehydroepiandrosterone on atherosclerosis in ovariectomized rabbits via alleviating inflammatory injury in endothelial cells. Atherosclerosis 214:47–57PubMedGoogle Scholar
  161. 161.
    Liu D, Dillon JS (2004) Dehydroepiandrosterone stimulates nitric oxide release in vascular endothelial cells: evidence for a cell surface receptor. Steroids 69:279–289PubMedGoogle Scholar
  162. 162.
    Hayashi T, Esaki T, Muto E, Kano H, Asai Y, Thakur NK, Sumi D, Jayachandran M, Iguchi A (2000) Dehydroepiandrosterone retards atherosclerosis formation through its conversion to estrogen: the possible role of nitric oxide. Arterioscler Thromb Vasc Biol 20:782–792PubMedGoogle Scholar
  163. 163.
    McCrohon JA, Death AK, Nakhla S, Jessup W, Handelsman DJ, Stanley KK, Celermajer DS (2000) Androgen receptor expression is greater in macrophages from male than from female donors. A sex difference with implications for atherogenesis Circulation 101:224–226PubMedGoogle Scholar
  164. 164.
    Bernini GP, Sgro’ M, Moretti A, Argenio GF, Barlascini CO, Cristofani R, Salvetti A (1999) Endogenous androgens and carotid intimal-medial thickness in women. J Clin Endocrinol Metab 84:2008–2012PubMedGoogle Scholar
  165. 165.
    Godia EC, Madhok R, Pittman J, Trocio S, Ramas R, Cabral D, Sacco RL, Rundek T (2007) Carotid artery distensibility: a reliability study. J Ultrasound Med 26:1157–1165PubMedPubMedCentralGoogle Scholar
  166. 166.
    London GM, Cohn JN (2002) Prognostic application of arterial stiffness: task forces. Am J Hypertens 15:754–758PubMedGoogle Scholar
  167. 167.
    Palombo C, Kozakova M (2016) Arterial stiffness, atherosclerosis and cardiovascular risk: Pathophysiologic mechanisms and emerging clinical indications. Vasc Pharmacol 77:1–7Google Scholar
  168. 168.
    Shufelt C, Elboudwarej O, Johnson BD, Mehta P, Bittner V, Braunstein G, Berga S, Stanczyk F, Dwyer K, Merz CN (2016) Carotid artery distensibility and hormone therapy and menopause: the Los Angeles Atherosclerosis Study. Menopause 23:150–157PubMedPubMedCentralGoogle Scholar
  169. 169.
    Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Kurioka S, Yano S, Sugimoto T (2008) Serum DHEA-S level is associated with the presence of atherosclerosis in postmenopausal women with type 2 diabetes mellitus. Endocr J 55:667–675PubMedGoogle Scholar
  170. 170.
    Aguirre GA, De Ita JR, de la Garza RG, Castilla-Cortazar I (2016) Insulin-like growth factor-1 deficiency and metabolic syndrome. J Transl Med 14:3PubMedPubMedCentralGoogle Scholar
  171. 171.
    Tagashira H, Bhuiyan S, Shioda N, Fukunaga K (2011) Distinct cardioprotective effects of 17β-estradiol and dehydroepiandrosterone on pressure overload-induced hypertrophy in ovariectomized female rats. Menopause 18:1317–1326PubMedGoogle Scholar
  172. 172.
    Rossier MF, Lenglet S, Vetterli L, Python M, Maturana A (2008) Corticosteroids and redox potential modulate spontaneous contractions in isolated rat ventricular cardiomyocytes. Hypertension 52:721–728PubMedGoogle Scholar
  173. 173.
    Lalevée N, Rebsamen MC, Barrère-Lemaire S, Perrier E, Nargeot J, Bénitah JP, Rossier MF (2005) Aldosterone increases T-type calcium channel expression and in vitro beating frequency in neonatal rat cardiomyocytes. Cardiovasc Res 67:216–224PubMedGoogle Scholar
  174. 174.
    Mannic T, Mouffok M, Python M, Yoshida T, Maturana AD, Vuilleumier N, Rossier MF (2013) DHEA prevents mineralo- and glucocorticoid receptor-induced chronotropic and hypertrophic actions in isolated rat cardiomyocytes. Endocrinology 154:1271–1281PubMedGoogle Scholar
  175. 175.
    Huang B, Qin D, Deng L, Boutjdir M, El Sherif N (2000) Reexpression of T-type Ca2+ channel gene and current in post-infarction remodeled rat left ventricle. Cardiovasc Res 46:442–449PubMedGoogle Scholar
  176. 176.
    Dunay GA, Paragi P, Sára L, Ács N, Balázs B, Ágoston V, Répás C, Ivanics T, Miklós Z (2015) Depressed calcium cycling contributes to lower ischemia tolerance in hearts of estrogen-deficient rats. Menopause 22:773–782PubMedGoogle Scholar
  177. 177.
    Barbagallo M, Shan J, Pang PK, Resnick LM (1995) Effects of dehydroepiandrosterone sulfate on cellular calcium responsiveness and vascular contractility. Hypertension 26:1065–1069PubMedGoogle Scholar
  178. 178.
    Usman M, Gillies CL, Khunti K, Davies MJ (2018) Effects of intensive interventions compared to standard care in people with type 2 diabetes and microalbuminuria on risk factors control and cardiovascular outcomes: a systematic review and meta-analysis of randomised controlled trials. Diabetes Res Clin Pract 146:76–84PubMedGoogle Scholar
  179. 179.
    Strain WD, Chaturvedi N, Bulpitt CJ, Rajkumar C, Shore AC (2005) Albumin excretion rate and cardiovascular risk: could the association be explained by early microvascular dysfunction? Diabetes 54:1816–1822PubMedGoogle Scholar
  180. 180.
    Roest M, Banga JD, Janssen WM, Grobbee DE, Sixma JJ, de Jong PE, de Zeeuw D, van Der Schouw YT (2001) Excessive urinary albumin levels are associated with future cardiovascular mortality in postmenopausal women. Circulation 103:3057–3061PubMedGoogle Scholar
  181. 181.
    Fukui M, Kitagawa Y, Nakamura N, Kadono M, Hasegawa G, Yoshikawa T (2004) Association between urinary albumin excretion and serum dehydroepiandrosterone sulfate concentration in male patients with type 2 diabetes: a possible link between urinary albumin excretion and cardiovascular disease. Diabetes Care 27:2893–2897PubMedGoogle Scholar
  182. 182.
    Fukui M, Ose H, Kitagawa Y, Yamazaki M, Hasegawa G, Yoshikawa T, Nakamura N (2007) Relationship between low serum endogenous androgen concentrations and arterial stiffness in men with type 2 diabetes mellitus. Metabolism 56:1167–1173PubMedGoogle Scholar
  183. 183.
    Fukui M, Ose H, Nakayama I, Hosoda H, Asano M, Kadono M, Mogami S, Hasegawa G, Yoshikawa T, Nakamura N (2007) Association between urinary albumin excretion and serum dehydroepiandrosterone sulfate concentrations in women with type 2 diabetes. Diabetes Care 30:1886–1888PubMedGoogle Scholar
  184. 184.
    Harrington LB, Marck BT, Wiggins KL, McKnight B, Heckbert SR, Woods NF, LaCroix AZ, Blondon M, Psaty BM, Rosendaal FR et al (2017) Cross-sectional association of endogenous steroid hormone, sex hormone-binding globulin, and precursor steroid levels with hemostatic factor levels in postmenopausal women. J Thromb Haemost 15:80–90PubMedPubMedCentralGoogle Scholar
  185. 185.
    Goel RM, Cappola AR (2011) Dehydroepiandrosterone sulfate and postmenopausal women. Curr Opin Endocrinol Diabetes Obes 18:171–176PubMedGoogle Scholar
  186. 186.
    Panjari M, Davis SR (2010) DHEA for postmenopausal women: a review of the evidence. Maturitas 66:172–179PubMedGoogle Scholar
  187. 187.
    Davis SR, Panjari M, Stanczyk FZ (2011) Clinical review: DHEA replacement for postmenopausal women. J Clin Endocrinol Metab 96:1642–1653PubMedGoogle Scholar
  188. 188.
    Elraiyah T, Sonbol MB, Wang Z, Khairalseed T, Asi N, Undavalli C, Nabhan M, Altayar O, Prokop L, Montori VM et al (2014) Clinical review: The benefits and harms of systemic dehydroepiandrosterone (DHEA) in postmenopausal women with normal adrenal function: a systematic review and meta-analysis. J Clin Endocrinol Metab 99:3536–3542PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, Faculty of Medical SciencesState University of CampinasCampinasBrazil
  2. 2.Department of Physiology and Biophysics, Institute of Biomedical ScienceUniversity of Sao PauloSao PauloBrazil
  3. 3.Department of NutritionUniversity of Mogi das CruzesSao PauloBrazil

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