Gender Differences in Cardiovascular Drugs

  • Amanda J. Stolarz
  • Nancy J. RuschEmail author


Many common cardiovascular drugs exhibit different therapeutic outcomes and adverse effects between women and men. The different responses may reflect gender-specific variances in drug sensitivities and pharmacokinetic profiles coupled to inherent differences in the underlying physiology of each sex. For example, women have a longer baseline QT interval, as measured by electrocardiogram, compared to men; hence, compared to men, women are more susceptible to lethal ventricular arrhythmias caused by drugs that prolong the QT interval. Equitable inclusion of women subjects in clinical drug trials will improve our knowledge base for assessing the gender- specific risk/benefit ratio for cardiovascular drugs and will enable us to consider gender as one factor in prescribing drugs and adjusting drug loading and maintenance dosages. This chapter reviews current evidence for gender- related differences in the responses to common cardiovascular drugs including statins, antiplatelet and antithrombotic agents, β-blockers, digoxin, calcium channel blockers, isosorbide mononitrate, aldosterone antagonists, and drugs associated with the long QT syndrome.


Cardiovascular Drugs Therapeutics Medications Gender Side effects Pharmacokinetics 


  1. 1.
    Bugiardini R, Yan AT, Yan RT, Fitchett D, Langer A, Manfrini O, Goodman SG. Factors influencing underutilization of evidence-based therapies in women. Eur Heart J. 2011;32:1337–44.CrossRefPubMedGoogle Scholar
  2. 2.
    Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol. 2001;2(6):349–51.CrossRefPubMedGoogle Scholar
  3. 3.
    Oertelt-Prigione S. The influence of sex and gender on the immune response. Autoimmun Rev. 2012;11(6-7):A479–85.CrossRefPubMedGoogle Scholar
  4. 4.
    Manteuffel M, Williams S, Chen W, Verbrugge RR, Pittman DG, Steinkellner A. Influence of patient sex and gender on medication use, adherence, and prescribing alignment with guidelines. J Womens Health. 2014;23(2):112–9.CrossRefGoogle Scholar
  5. 5.
    Johansen ME, Hefner JL, Foraker RE. Antiplatelet and statin use in US patients with coronary artery disease categorized by race/ethnicity and gender, 2003 to 2012. Am J Cardiol. 2015;115(11):1507–12. [Epub ahead of print].CrossRefPubMedGoogle Scholar
  6. 6.
    Mattison D. Cardiovascular medications during pregnancy. In: Mattison D, editor. Clinical pharmacology during pregnancy. Academic Press; 2013; Chpt 18, p. 275–94.Google Scholar
  7. 7.
    Whitley HP, Lindsey W. Sex-based differences in drug activity. Am Fam Physician. 2009;80(11):1255–8.Google Scholar
  8. 8.
    Anderson GD. Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics. J Womens Health. 2005;14(1):19–29.CrossRefGoogle Scholar
  9. 9.
    Regitz-Zagrosek V. Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nat Rev Drug Discov. 2006;5(5):425–38.CrossRefPubMedGoogle Scholar
  10. 10.
    Kimura T, Higaki K. Gastrointestinal transit and drug absorption. Biol Pharm Bull. 2002;25(2):149–64.CrossRefPubMedGoogle Scholar
  11. 11.
    Fleisher D, Li C, Zhou Y, Pao LH, Karim A. Drug, meal, and formulation interactions influencing drug absorption after oral administration. Clinical implications. Clin Pharmacokinet. 1999;36(3):233–54.CrossRefPubMedGoogle Scholar
  12. 12.
    Mojaverian P, Rocci ML Jr, Conner DP, Abrams WB, Vlasses PH. Effect of food on the absorption of enteric coated aspirin: correlation with gastric residence time. Clin Pharmacol Ther. 1987;41(1):11–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Schwartz JB. The current state of knowledge on age, sex, and their interactions on clinical pharmacology. Clin Pharmacol Ther. 2007;82(1):87–96.CrossRefPubMedGoogle Scholar
  14. 14.
    Hagg S, Spigset O, Dahlqvist R. Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers. Br J Clin Pharmacol. 2001;51:169–73.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Yukawa E, Honda T, Ohdo S, Higuchi S, Aoyama T. Population-based investigation of relative clearance of digoxin in Japanese patients by multiple trough screen analysis: an update. J Clin Pharmacol. 1997;37(2):92–100.CrossRefPubMedGoogle Scholar
  16. 16.
    Desai H, Hollingsworth PW, Chugh AR. Statins and aspirin: do they really work in women? Am J Cardiovasc Drugs. 2015;15(3):151–62. Scholar
  17. 17.
    Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89–118. Scholar
  18. 18.
    Stead LG, Vaidyanathan L, Kumar G, Fellolio MF, Brown RD, Suravaram S, Enduri S, Gilmore RM, Decker WW. Statins in ischemic stroke: just low-density lipoprotein lowering or more? J Stroke Cerebrovas Dis. 2009;18(2):124–7.CrossRefGoogle Scholar
  19. 19.
    Pawelczyk M, Chmielewski H, Kaczorowska B, Przybyla M, Baj Z. The influence of statin therapy on platelet activity markers in hyperlipidemic patients after ischemic stroke. Arch Med Sci. 2015;11(1):115–21.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Antonopoulos AS, Margaritis M, Lee R, Channon K, Antoniades C. Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials. Curr Pharm Des. 2012;18:1519–30.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Blanco-Colio LM, Tunon J, Martin-Ventura JL, Egido J. Anti-inflammatory and immunomodulatory effects of statins. Kidney Int. 2003;63:12–23.CrossRefPubMedGoogle Scholar
  22. 22.
    McSweeney JC, Rosenfeld AG, Abel WM, Braun LT, Burke LE, Daugherty SL, Fletcher GF, Mehta LS, Pettey C, Reckelhoff JF. Preventing and experiencing ischemic heart disease as a woman: state of the science: a statement for healthcare professionals from the American Heart Association. Circulation. 2016;133(13):1302–31. Scholar
  23. 23.
    Culver AL, Ockene IS, Balasubramanian R, Olendzki BC, Sepavich DM, Wactawski-Wende J, Manson JE, Qiao Y, Liu S, Merriam PA, Rahilly-Tierny C, Thomas F, Berger JS, Ockene JK, Curb JD, Ma Y. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Intern Med. 2012;172(2):144–52. Scholar
  24. 24.
    Bang CN, Okin PM. Statin treatment, new-onset diabetes, and other adverse effects: a systematic review. Curr Cardiol Rep. 2014;16(3):461–4. CrossRefPubMedGoogle Scholar
  25. 25.
    Truong QA, Murphy SA, McCabe CH, Armani A, Cannon CP, Group TS. Benefit of intensive statin therapy in women: results from PROVE IT-TIMI 22. Circ Cardiovasc Qual Outcomes. 2011;4(3):328–36. Scholar
  26. 26.
    Basili S, Raparelli V, Proietti M, Tanzilli G, Franconi F. The impact of sex and gender on the efficacy of antiplatelet therapy: the female perspective. J Atheroscler Thromb. 2015;22:109–25.CrossRefPubMedGoogle Scholar
  27. 27.
    Awtry EH, Loscalzo J. Aspirin. Circulation. 2000;101:1206–18.CrossRefPubMedGoogle Scholar
  28. 28.
    Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA. 2006;295(3):306–13.CrossRefPubMedGoogle Scholar
  29. 29.
    Meyer DM, Eastwood JA, Copton MP, Gylys K, Zivin JA, Ovbiagele B. Sex differences in antiplatelet response in ischemic stroke. J Womens Health. (Lond.). 2011;7(4):465–74.CrossRefGoogle Scholar
  30. 30.
    Buchanan MR, Rischke JA, Butt R, Turpie AG, Hirsh J, Rosenfeld J, et al. The sex-related differences in aspirin pharmacokinetics in rabbits and man and its relationship to antiplatelet effects. Thromb Res. 1983;29:125–39.CrossRefPubMedGoogle Scholar
  31. 31.
    Samad Z, Boyle S, Ersboll M, Vora AN, Zhang Y, Becker RC, Williams R, Kuhn C, Ortel TL, Rogers JG, OConnor CM, Velzquez JW. Sex differences in platelet reactivity and cardiovascular and pyschological response to mental stress in patients with stable ischemic heart disease. J Am Coll Cardiol. 2014;64:1669–78.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Bray PF, Howard TD, Vittinghoff E, Sane DC, Herrington DM. Effect of genetic variations in platelet glycoproteins Iba and VI on the risk of coronary heart disease events in postmenopausal women taking hormone therapy. Blood. 2007;109(5):1862–9.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Nakano Y, Oshima T, Ozono R, Ueda A, Oue Y, Matsuura H, Sanada M, Ohama K, Chayama K, Kambe M. Estrogen replacement suppresses function of thrombin stimulated platelets by inhibiting Ca2+ influx and raising cyclic adenosine monophosphate. Cardiovasc Res. 2002;53:634–41.CrossRefPubMedGoogle Scholar
  34. 34.
    Miller VM, Jayachandran M, Hashimoto K, Heit JA, Owen WG. Estrogen, inflammation, and platelet phenotype. Gend Med. 2008;5(Suppl A):S91–S102.CrossRefPubMedGoogle Scholar
  35. 35.
    Godley RW, Hernandez-Vila E. Aspirin for primary and secondary prevention of cardiovascular disease. Tex Heart Inst J. 2016;43(4):318–9. Scholar
  36. 36.
    Viles-Gonzalez JF, Fuster V, Badimon JJ. Atherothrombosis: a widespread disease with unpredictable and life-threatening consequences. Eur Heart J. 2004;25:1197–207.CrossRefPubMedGoogle Scholar
  37. 37.
    Capodanno D, Angiolillo DJ. Impact of race and gender on antithrombotic therapy. Thromb Haemost. 2012;104:471–84.CrossRefGoogle Scholar
  38. 38.
    Granger CB, Hirsh J, Califf RM, Col J, White HD, Betriu A, Woodlief LH, Lee KL, Bovill EG, Simes RJ, Topol EJ. For the GUSTO-1 Investigators. Activated partial thromboplastin time and outcome after thrombolytic therapy for acute myocardial infarction. Circulation. 1996;93:870–8.CrossRefPubMedGoogle Scholar
  39. 39.
    Weaver WD, White HD, Wilcox RG, Aylward PE, Morris D, Guerci A, Ohman EM, Barbash GI, Betriu A, Sadowski Z, Topol EJ, Califf RM. Comparisons of characteristics and outcomes among women and men with acute myocardial infarction treated with thrombolytic therapy. GUSTO-I Investigators. JAMA. 1996;275(10):777–82.CrossRefPubMedGoogle Scholar
  40. 40.
    Woodfield SL, Lundergan CF, Reiner JS, Thompson MA, Rohrbeck SC, Deychak Y, Smith JO, Burton JR, McCarthy WF, Califf RM, White HD, Weaver WD, Topol EJ, Ross AM. Gender and acute myocardial infarction: is there a different response to thrombolysis? J Am Coll Cardiol. 1997;29:35–42.CrossRefPubMedGoogle Scholar
  41. 41.
    Van de Werf F, Barron HV, Armstrong PW, Granger CB, Berioli S, Barbash G, Pehrsson K, Verheugt FW, Meyer J, Betriu A, Califf RM, Li X, Fox NL. ASSENT-2 Investigators. Assessment of the safety and efficacy of a new thrombolytic. Incidence and predictors of bleeding events after fibrinolytic therapy with fibrin-specific agents: a comparison of TNK-tPA and rt-PA. Eur Heart J. 2001;22:2253–61.CrossRefPubMedGoogle Scholar
  42. 42.
    Berkowitz SD, Granger CB, Pieper KS, Lee KL, Gore JM, Simons M, Armstrong PW, Topol EJ, Califf RM. Global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (GUSTO) I Investigators. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. Circulation. 1997;95:2508–16.CrossRefGoogle Scholar
  43. 43.
    Gheorghiade M, Adams KF, Colucci WS. Digoxin in the management of cardiovascular disorders. Circulation. 2004;109:2959–64.CrossRefPubMedGoogle Scholar
  44. 44.
    The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336(8):525–33.CrossRefGoogle Scholar
  45. 45.
    Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med. 2002;347(18):1403–11.CrossRefPubMedGoogle Scholar
  46. 46.
    Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJV, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WHW, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA guideline for the management of heart failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–239.CrossRefGoogle Scholar
  47. 47.
    Helfand M, Peterson K, Christensen V, Dana T, Thakurta S. Drug class review: beta adrenergic blockers: final report update 4. Portland (OR): Oregon Health & Science University; 2009. Scholar
  48. 48.
    Luzier AB, Killian A, Wilton JH, Wilson MF, Forrest A, Kazierad DJ. Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers. Clin Pharm Ther. 1999;66(6):594–601.CrossRefGoogle Scholar
  49. 49.
    Cocco G, Chu D. The anti-ischemic effect of metoprolol in patients with chronic angina pectoris is gender-specific. Cardiology. 2006;106:147–53.CrossRefPubMedGoogle Scholar
  50. 50.
    The MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomised intervention trial in congestive heart failure (MERITHF). Lancet. 1999;353:2001–7.CrossRefGoogle Scholar
  51. 51.
    Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U. S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996;334:1349–55.CrossRefGoogle Scholar
  52. 52.
    Simon T, Mary-Krause M, Funck-Brentano C, Jaillon P. Sex differences in the prognosis of congestive heart failure: results from the cardiac insufficiency bisoprolol study (CIBIS II). Circulation. 2001;103:375–80.CrossRefPubMedGoogle Scholar
  53. 53.
    CIBISII1999. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9–13.CrossRefGoogle Scholar
  54. 54.
    Ghali JK, Pina IL, Gottlieb SS, Deedwania PC, Wikstrand JC, Metoprolol CR. XL in female patients with heart failure: analysis of the experience in Metoprolol extended-release randomized intervention trial in heart failure (MERIT-HF). Circulation. 2000;105:1585–91.CrossRefGoogle Scholar
  55. 55.
    Leenhardt A, Coumel P, Slama R. Torsades de pointes. J Cardiovasc Electrophysiol. 1992;3:281–92.CrossRefGoogle Scholar
  56. 56.
    Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The long QT syndrome: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis. 1988;31:115–72.CrossRefPubMedGoogle Scholar
  57. 57.
    Merri M, Benhorin J, Alberti M, Locati E, Moss A. Electrocardiographic quantitation of ventricular repolarization. Circulation. 1989;80:1301–8.CrossRefPubMedGoogle Scholar
  58. 58.
    Stramba-Badiale M, Locati EH, Martinelli A, Courville J, Schwartz PJ. Gender and the relationship between ventricular repolarization and cardiac cycle length during 24-h Holter recordings. Eur Heart J. 1997;18:1000–6.CrossRefPubMedGoogle Scholar
  59. 59.
    Rautaharju PM, Zhou SH, Wong S, Calhoun HP, Berenson GS, Prineas R, Davignon A. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol. 1992;8:690–5.PubMedGoogle Scholar
  60. 60.
    Makkar RR, Fromm BS, Steinman RT, Meissner MD, Lehmann MH. Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA. 1993;270(21):2590–7.CrossRefPubMedGoogle Scholar
  61. 61.
    Lehmann MH, Hardy S, Archibald D, Quart B, MacNeil DJ. Sex difference in risk of torsade de pointes with d,l-sotalol. Circulation. 1996;94:2535–41.CrossRefPubMedGoogle Scholar
  62. 62.
    Sadlak T, Shufelt C, Iribarren C, Bairey Merz CN. Sex hormones and the QT interval: a review. J Womens Health. 2012;21(9):933–41.CrossRefGoogle Scholar
  63. 63.
    Nakagawa M, Ooie T, Takahashi N, Taniguchi Y, Anan F, Yonemochi H, Saikawa T. Influence of menstrual cycle on QT interval dynamics. PACE. 2006;29:607–13.CrossRefPubMedGoogle Scholar
  64. 64.
    Rodriguez I, Kilborn MJ, Liu XK, Pezzullo JC, Woosley RL, Drug-induced QT. Prolongation in women during the menstrual cycle. JAMA. 2001;285:1322–6.CrossRefPubMedGoogle Scholar
  65. 65.
    Fazio G, Vernuccio F, Grutta G, Lo Re G. Drugs to be avoided in patients with long QT syndrome: focus on the anaesthesiological management. World J Cardiol. 2013;5(4):87–93.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Thompson KA, Murray JJ, Blair IA, Woosley RL, Roden DM. Plasma concentrations of quinidine, its major metabolites, and dihydroquinidine in patients with torsades de pointes. Clin Pharmacol Ther. 1988;43:636–42.CrossRefPubMedGoogle Scholar
  67. 67.
    Darpo B, Karnad DR, Balilini F, Florlan J, Garnett CE, Korthari S, Panicker GK, Sarapa N. Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol. Br J Clin Pharmacol. 2013;77(3):522–31.CrossRefGoogle Scholar
  68. 68.
    Nakagawa M, Ooie T, Ou B, Ichinose M, Takahashi M, Hara M, Yonemochi H, Saikawa T. Gender differences in autonomic modulation of ventricular repolarization in humans. J Cardiovasc Electrophysiol. 2005;16:278–84.CrossRefPubMedGoogle Scholar
  69. 69.
    Conrath CE, Wilde AAM, Jongbloed RJE, Alders M, van Langen IM, van Tintelen JP, Doevendans PA, Opthof T. Gender differences in the long QT syndrome: effects of β-adrenocepter blockade. Cardiovasc Res. 2002;53:770–6.CrossRefPubMedGoogle Scholar
  70. 70.
    Dadashzadeha S, Javadiana B, Sadeghianb S. The effect of gender on the pharmacokinetics of verapamil and norverapamil in humans. Biopharm Drug Dispos. 2006;27:329–34.CrossRefGoogle Scholar
  71. 71.
    Abad-Santos F, Novalbos J, Gálvez-Múgica MA, Gallego-Sandín S, Almeida S, Vallée F, García AG. Assessment of sex differences in pharmacokinetics and pharmacodynamics of amlodipine in a bioequivalence study. Pharmacol Res. 2005;51(5):445–52.CrossRefPubMedGoogle Scholar
  72. 72.
    Kloner RA, Sowers JR, DiBona GF, Gaffney M, Wein M. Sex- and age-related antihypertensive effects of amlodipine. The Amlodipine Cardiovascular Community Trial Study Group. Am J Cardiol. 1996;77(9):713–22.CrossRefPubMedGoogle Scholar
  73. 73.
    Spratt KA. Sex- and age-related antihypertensive effects of amlodipine. Am J Cardiol. 1997;79(6):843–4.CrossRefPubMedGoogle Scholar
  74. 74.
    Vree TB, Dammers E, Valducci R. Sex-related differences in the pharmacokinetics of isosorbide-5-mononitrate (60 mg) after repeated oral administration of two different original prolonged release formulations. Int J Clin Pharmacol Ther. 2004;42(8):463–72.CrossRefPubMedGoogle Scholar
  75. 75.
    Li EC, Heran BS, Wright JM. Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension. Cochrane Database Syst Rev. 2014;8:CD009096. CrossRefGoogle Scholar
  76. 76.
    Olde Engberink RH, Frenkel WJ, van den Bogaard B, Brewster LM, Vogt L, van den Born BJ. Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis. Hypertension. 2015;65(5):1033–40. Scholar
  77. 77.
    Ljungman C, Kahan T, Schioler L, Hjerpe P, Hasselstrom J, Wettermark B, Bostrom KB, Manhem K. Gender differences in antihypertensive drug treatment: results from the Swedish Primary Care Cardiovascular Database (SPCCD). J Amer Soc Hypertens. 2014;8(12):882–90.CrossRefGoogle Scholar
  78. 78.
    Ljungman C, Kahan T, Schiöler L, Hjerpe P, Wettermark B, Boström KB, Manhem K. Antihypertensive treatment and control according to gender, education, country of birth and psychiatric disorder: the Swedish Primary Care Cardiovascular Database (SPCCD). J Hum Hypertens. 2015;29(6):385–93. Scholar
  79. 79.
    Li DK, Yang C, Andrade S, Tavares V, Ferber JR. Maternal exposure to angiotensin converting enzyme inhibitors in the first trimester and risk of malformations in offspring: a retrospective cohort study. BMJ. 2011;343:d5931. Scholar
  80. 80.
    Walfisch A, Al-maawali A, Moretti ME, Nickel C, Koren G. Teratogenicity of angiotensin converting enzyme inhibitors or receptor blockers. J Obstet Gynaecol. 2011;31(6):465–72. Scholar
  81. 81.
    Moretti ME, Caprara D, Drehuta I, Yeung E, Cheung S, Federico L, Koren G. The fetal safety of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. Obstet Gynecol Int. 2012;2012:658310. Scholar
  82. 82.
    Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, Hall K, Ray WA. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006;354(23):2443–51.CrossRefPubMedGoogle Scholar
  83. 83.
    Os I, Bratland B, Dahlof B, Gisholt K, Syvertsen JO, Tretli S. Female preponderance for lisinopril-induced cough in hypertension. Am J Hypertens. 1994;7:1012–5.CrossRefPubMedGoogle Scholar
  84. 84.
    Barber J, McKeever TM, McDowell SE, Clayton JA, Ferner RE, Gordon RD, Stowasser M, O'Shaughnessy KM, Hall IP, Glover M. A systematic review and meta-analysis of thiazide-induced hyponatraemia: time to reconsider electrolyte monitoring regimens after thiazide initiation? Br J Clin Pharmacol. 2015;79(4):566–77. Scholar
  85. 85.
    Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709–17.CrossRefPubMedGoogle Scholar
  86. 86.
    Maron BA, Leopold JA. Aldosterone receptor antagonists: effective but often forgotten. Circulation. 2010;121:934–9.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Berbenetz NM, Mrkobrada M. Mineralocorticoid receptor antagonists for heart failure: systematic review and meta-analysis. BMC Cardiovasc Disord. 2016;16:246. Scholar
  88. 88.
    Nuttall FQ, Warrier RS, Gannon MC. Gynecomastia and drugs: a critical evaluation of the literature. Eur J Clin Pharmacol. 2015;71(5):569–78. Scholar
  89. 89.
    Jeunemaitre X, Chatellier G, Kreft-Jais C, Charru A, Devries C, Plouin PF, Corvo P, Menard J. Efficacy and tolerance of spironolactone in essential hypertension. Am J Cardiol. 1987;60(10):820–5.CrossRefPubMedGoogle Scholar
  90. 90.
    Rose LI, Underwood RH, Newmark SR, Kisch ES, Williams GH. Pathophysiology of spironolactone-induced gynecomastia. Ann Intern Med. 1977;87(4):398–403.CrossRefPubMedGoogle Scholar
  91. 91.
    Unger CA. Hormone therapy for transgender patients. Transl Androl Urol. 2016;5(6):877–84. Scholar
  92. 92.
    Harvey RE, Coffman KE, Miller VM. Women-specific factors to consider in risk, diagnosis and treatment of cardiovascular disease. Womens Health (Lond Engl). 2015;11(2):239–57. CrossRefGoogle Scholar
  93. 93.
    Shatzel JJ, Connelly KJ, DeLoughery TG. Thrombotic issues in transgender medicine: a review. Am J Hematol. 2017;92:204–8. Scholar
  94. 94.
    Dous GV, Grodman R, Mornan A, Otterbeck P, Grigos A. Menopausal hormone treatment in postmenopausal women: risks and benefits. South Med J. 2014;107(11):689–95. Scholar
  95. 95.
    Deutsch MB, Bhakri V, Kubicek K. Effects of cross-sex hormone treatment on transgender women and men. Obstet Gynecol. 2015;125(3):605–10. Scholar
  96. 96.
    Gooren LJ, Wierckx K, Giltay EJ. Cardiovascular disease in transsexual persons treated with cross-sex hormones: reversal of the traditional sex difference in cardiovascular disease pattern. Eur J Endocrinol. 2014;170(6):809–19. Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pharmacology and ToxicologyColleges of Medicine and Pharmacy, University of Arkansas for Medical SciencesLittle RockUSA

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