Abstract
The influence of biological sex on pharmacokinetics and pharmacodynamics has been previously described for each step of the metabolic cascade of pharmaceuticals. Women and men display differences in distribution, metabolism, and excretion of drugs for several biologic reasons. Estrogens are relevant in these processes, but cannot be regarded as the only responsible mechanism. Sex differences in the incidence of adverse drug reactions and pharmacotoxicity have also been reported for several classes of drugs and specifically for several cardiovascular preparations. Given the high incidence of cardiovascular conditions and thus the broad use of these drugs in the general population, these reports have to be considered of relevance to public health. Nonetheless, increased knowledge has not translated into the development and implementation of gender-specific pharmacologic guidelines which appear as the only effective strategy to minimize the incidence of sex-specific side effects and adverse drug reactions. In the present review, we analyze the basic aspects of sex-specific pharmacodynamics and present several examples of gender dimorphism in cardiovascular drugs. We also suggest measures to analyze and possibly improve current therapeutic strategies.
Similar content being viewed by others
References
Alexander, K. P., Chen, A. Y., Newby, L. K., Schwartz, J. B., Redberg, R. F., Hochman, J. S., et al. (2006). Sex differences in major bleeding with glycoprotein IIb/IIIa inhibitors: results from the CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines) initiative. Circulation, 114(13), 1380–1387.
Anderson, G. D. (2005). Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics. Journal of Womens Health, 14(1), 19–29.
Anthony, M. (2005). Male/female differences in pharmacology: safety issues with QT-prolonging drugs. Journal of Womens Health, 14(1), 47–52.
Arias-Loza, P. A., Jazbutyte, V., & Pelzer, T. (2008). Genetic and pharmacologic strategies to determine the function of estrogen receptor alpha and estrogen receptor beta in cardiovascular system. Gender Medicine, 5(Suppl A), S34–S45.
Baraona, E., Abittan, C. S., Dohmen, K., Moretti, M., Pozzato, G., Chayes, Z. W., et al. (2001). Gender differences in pharmacokinetics of alcohol. Alcoholism, Clinical and Experimental Research, 25(4), 502–507.
CM, Brinkman-Van der Linden, Havenaar, E. C., Van Ommen, C. R., Van Kamp, G. J., Gooren, L. J., & Van Dijk, W. (1996). Oral estrogen treatment induces a decrease in expression of sialyl Lewis x on alpha 1-acid glycoprotein in females and male-to-female transsexuals. Glycobiology, 6(4), 407–412.
Brown, D. A., Lynch, J. M., Armstrong, C. J., Caruso, N. M., Ehlers, L. B., Johnson, M. S., et al. (2005). Susceptibility of the heart to ischaemia-reperfusion injury and exercise-induced cardioprotection are sex-dependent in the rat. Journal of Physiology, 564(Pt 2), 619–630.
Bruno, R., Vivier, N., Montay, G., Le Liboux, A., Powe, L. K., Delumeau, J. C., et al. (1997). Population pharmacokinetics of riluzole in patients with amyotrophic lateral sclerosis. Clinical Pharmacology and Therapeutics, 62(5), 518–526.
Camper-Kirby, D., Welch, S., Walker, A., Shiraishi, I., Setchell, K. D., Schaefer, E., et al. (2001). Myocardial Akt activation and gender: increased nuclear activity in females versus males. Circulation Research, 88(10), 1020–1027.
Carroll, J. D., Carroll, E. P., Feldman, T., Ward, D. M., Lang, R. M., McGaughey, D., et al. (1992). Sex-associated differences in left ventricular function in aortic stenosis of the elderly. Circulation, 86(4), 1099–1107.
Cerrutti, J. A., Brandoni, A., Quaglia, N. B., & Torres, A. M. (2002). Sex differences in p-aminohippuric acid transport in rat kidney: role of membrane fluidity and expression of OAT1. Molecular and Cellular Biochemistry, 233(1–2), 175–179.
Ciana, P., Raviscioni, M., Mussi, P., Vegeto, E., Que, I., Parker, M. G., et al. (2003). In vivo imaging of transcriptionally active estrogen receptors. Natural Medicines, 9(1), 82–86.
Drici, M. D., Knollmann, B. C., Wang, W. X., & Woosley, R. L. (1998). Cardiac actions of erythromycin: influence of female sex. JAMA, 280(20), 1774–1776.
Du, X. J. (2004). Gender modulates cardiac phenotype development in genetically modified mice. Cardiovascular Research, 63(3), 510–519.
Edwards, D. P. (2005). Regulation of signal transduction pathways by estrogen and progesterone. Annual Review of Physiology, 67, 335–376.
Ereshefsky, L., Saklad, S. R., Watanabe, M. D., Davis, C. M., & Jann, M. W. (1991). Thiothixene pharmacokinetic interactions: a study of hepatic enzyme inducers, clearance inhibitors, and demographic variables. Journal of Clinical Psychopharmacology, 11(5), 296–301.
Fitzgerald, P. T., & Ackerman, M. J. (2005). Drug-induced torsades de pointes: the evolving role of pharmacogenetics. Heart Rhythm, 2(2 Suppl), S30–S37.
Franconi, F., Brunelleschi, S., Steardo, L., & Cuomo, V. (2007). Gender differences in drug responses. Pharmacological Research, 55(2), 81–95.
Frezza, M., di Padova, C., Pozzato, G., Terpin, M., Baraona, E., & Lieber, C. S. (1990). High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. New England Journal of Medicine, 322(2), 95–99.
Gandhi, M., Aweeka, F., Greenblatt, R. M., & Blaschke, T. F. (2004). Sex differences in pharmacokinetics and pharmacodynamics. Annual Review Pharmacology and Toxicology, 44, 499–523.
Gaudry, S. E., Sitar, D. S., Smyth, D. D., McKenzie, J. K., & Aoki, F. Y. (1993). Gender and age as factors in the inhibition of renal clearance of amantadine by quinine and quinidine. Clinical Pharmacology and Therapeutics, 54(1), 23–27.
Ghali, J. K., Pina, I. L., Gottlieb, S. S., Deedwania, P. C., & Wikstrand, J. C. (2002). 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, 105(13), 1585–1591.
Gochfeld, M. (2007). Framework for gender differences in human and animal toxicology. Environmental Research, 104(1), 4–21.
Grohe, C., Kahlert, S., Lobbert, K., & Vetter, H. (1998). Expression of oestrogen receptor alpha and beta in rat heart: role of local oestrogen synthesis. Journal of Endocrinology, 156(2), R1–R7.
Guengerich, F. P. (1999). Cytochrome P-450 3A4: regulation and role in drug metabolism. Annual Review of Pharmacology and Toxicology, 39, 1–17.
Haram, K., Augensen, K., & Elsayed, S. (1983). Serum protein pattern in normal pregnancy with special reference to acute-phase reactants. British Journal of Obstetrics and Gynaecology, 90(2), 139–145.
Humphries, K. H., Kerr, C. R., Connolly, S. J., Klein, G., Boone, J. A., Green, M., et al. (2001). New-onset atrial fibrillation: sex differences in presentation, treatment, and outcome. Circulation, 103(19), 2365–2370.
Hunt, C. M., Westerkam, W. R., & Stave, G. M. (1992). Effect of age and gender on the activity of human hepatic CYP3A. Biochemical Pharmacology, 44(2), 275–283.
Hutson, W. R., Roehrkasse, R. L., & Wald, A. (1989). Influence of gender and menopause on gastric emptying and motility. Gastroenterology, 96(1), 11–17.
Kadokami, T., McTiernan, C. F., Kubota, T., Frye, C. S., & Feldman, A. M. (2000). Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression. Journal of Clinical Investigation, 106(4), 589–597.
Kalow, W., & Tang, B. K. (1991). Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. Clinical Pharmacology and Therapeutics, 50(5 Pt 1), 508–519.
Kendall, M. J., Quarterman, C. P., Jack, D. B., & Beeley, L. (1982). Metoprolol pharmacokinetics and the oral contraceptive pill. British Journal of Clinical Pharmacology, 14(1), 120–122.
Labbe, L., Sirois, C., Pilote, S., Arseneault, M., Robitaille, N. M., Turgeon, J., et al. (2000). Effect of gender, sex hormones, time variables and physiological urinary pH on apparent CYP2D6 activity as assessed by metabolic ratios of marker substrates. Pharmacogenetics, 10(5), 425–438.
Lan, L. B., Dalton, J. T., & Schuetz, E. G. (2000). Mdr1 limits CYP3A metabolism in vivo. Molecular Pharmacology, 58(4), 863–869.
Lees, J., Hallak, J. E., Deakin, J. F., & Dursun, S. M. (2004). Gender differences and the effects of ketamine in healthy volunteers. Journal of Psychopharmacology, 18(3), 337–339.
Leinwand, L. A. (2003). Sex is a potent modifier of the cardiovascular system. Journal of Clinical Investigation, 112(3), 302–307.
Litwin, S. E., Katz, S. E., Litwin, C. M., Morgan, J. P., & Douglas, P. S. (1999). Gender differences in postinfarction left ventricular remodeling. Cardiology, 91(3), 173–183.
Mahmoodzadeh, S., Eder, S., Nordmeyer, J., Ehler, E., Huber, O., Martus, P., et al. (2006). Estrogen receptor alpha up-regulation and redistribution in human heart failure. FASEB Journal, 20(7), 926–934.
Makkar, R. R., Fromm, B. S., Steinman, R. T., Meissner, M. D., & Lehmann, M. H. (1993). Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs. JAMA, 270(21), 2590–2597.
Mearadji, B., Penning, C., Vu, M. K., van der Schaar, P. J., van Petersen, A. S., Kamerling, I. M., et al. (2001). Influence of gender on proximal gastric motor and sensory function. American Journal of Gastroenterology, 96(7), 2066–2073.
Mendelsohn, M. E., & Karas, R. H. (1999). The protective effects of estrogen on the cardiovascular system. New England Journal of Medicine, 340(23), 1801–1811.
Mendelsohn, M. E., & Karas, R. H. (2005). Molecular and cellular basis of cardiovascular gender differences. Science, 308(5728), 1583–1587.
Metivier, R., Penot, G., Hubner, M. R., Reid, G., Brand, H., Kos, M., et al. (2003). Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell, 115(6), 751–763.
Mosca, L., Banka, C. L., Benjamin, E. J., Berra, K., Bushnell, C., Dolor, R. J., et al. (2007). Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation, 115(11), 1481–1501.
Nordmeyer, J., Eder, S., Mahmoodzadeh, S., Martus, P., Fielitz, J., Bass, J., et al. (2004). Upregulation of myocardial estrogen receptors in human aortic stenosis. Circulation, 110(20), 3270–3275.
Nuedling, S., Karas, R. H., Mendelsohn, M. E., Katzenellenbogen, J. A., Katzenellenbogen, B. S., Meyer, R., et al. (2001). Activation of estrogen receptor beta is a prerequisite for estrogen-dependent upregulation of nitric oxide synthases in neonatal rat cardiac myocytes. FEBS Letters, 502(3), 103–108.
Os, I., Bratland, B., Dahlof, B., Gisholt, K., Syvertsen, J. O., & Tretli, S. (1992). Female sex as an important determinant of lisinopril-induced cough. Lancet, 339(8789), 372.
Pitt, B., Zannad, F., Remme, W. J., Cody, R., Castaigne, A., Perez, A., et al. (1999). The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. New England Journal of Medicine, 341(10), 709–717.
Rathore, S. S., Curtis, J. P., Wang, Y., Bristow, M. R., & Krumholz, H. M. (2003). Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA, 289(7), 871–878.
Rathore, S. S., Wang, Y., & Krumholz, H. M. (2002). Sex-based differences in the effect of digoxin for the treatment of heart failure. New England Journal of Medicine, 347(18), 1403–1411.
Regitz-Zagrosek, V. (2006). Therapeutic implications of the gender-specific aspects of cardiovascular disease. Nature Reviews. Drug Discovery, 5(5), 425–438.
Regitz-Zagrosek, V., Lehmkuhl, E., Lehmkuhl, H. B., & Hetzer, R. (2004). Gender aspects in heart failure. Pathophysiology and medical therapy. Archives Des Maladies Du Coeur Et Des Vaisseaux, 97(9), 899–908.
Ridker, P. M., Cook, N. R., Lee, I. M., Gordon, D., Gaziano, J. M., Manson, J. E., et al. (2005). A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. New England Journal of Medicine, 352(13), 1293–1304.
Rubanyi, G. M., Kauser, K., & Johns, A. (2002). Role of estrogen receptors in the vascular system. Vascular Pharmacology, 38(2), 81–88.
Schmidt, R., Baumann, F., Hanschmann, H., Geissler, F., & Preiss, R. (2001). Gender difference in ifosfamide metabolism by human liver microsomes. European Journal of Drug Metabolism and Pharmacokinetics, 26(3), 193–200.
Schwartz, J. B. (2003). The influence of sex on pharmacokinetics. Clinical Pharmacokinetics, 42(2), 107–121.
Singer, A. J., & Brandt, L. J. (1991). Pathophysiology of the gastrointestinal tract during pregnancy. American Journal of Gastroenterology, 86(12), 1695–1712.
Skaanild, M. T., & Friis, C. (1999). Cytochrome P450 sex differences in minipigs and conventional pigs. Pharmacology and Toxicology, 85(4), 174–180.
Smith, C. L., Conneely, O. M., & O'Malley, B. W. (1993). Modulation of the ligand-independent activation of the human estrogen receptor by hormone and antihormone. Proceedings of the National Academy of Sciences of the United States of America, 90(13), 6120–6124.
Tanaka, E. (1998). Clinically important pharmacokinetic drug-drug interactions: role of cytochrome P450 enzymes. Journal of Clinical Pharmacy and Therapeutics, 23(6), 403–416.
Tatchum-Talom, R., Eyster, K. M., & Martin, D. S. (2005). Sexual dimorphism in angiotensin II-induced hypertension and vascular alterations. Canadian Journal of Physiology and Pharmacology, 83(5), 413–422.
Tuck, C. H., Holleran, S., & Berglund, L. (1997). Hormonal regulation of lipoprotein(a) levels: effects of estrogen replacement therapy on lipoprotein(a) and acute phase reactants in postmenopausal women. Arteriosclerosis, Thrombosis, and Vascular Biology, 17(9), 1822–1829.
Walle, T., Walle, K., Mathur, R. S., Palesch, Y. Y., & Conradi, E. C. (1994). Propranolol metabolism in normal subjects: association with sex steroid hormones. Clinical Pharmacology and Therapeutics, 56(2), 127–132.
Weinberg, E. O., Mirotsou, M., Gannon, J., Dzau, V. J., Lee, R. T., & Pratt, R. E. (2003). Sex dependence and temporal dependence of the left ventricular genomic response to pressure overload. Physiological Genomics, 12(2), 113–127.
Wilson, K. (1984). Sex-related differences in drug disposition in man. Clinical Pharmacokinetics, 9(3), 189–202.
Wing, L. M., Reid, C. M., Ryan, P., Beilin, L. J., Brown, M. A., Jennings, G. L., et al. (2003). A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. New England Journal of Medicine, 348(7), 583–592.
Wolbrette, D., Naccarelli, G., Curtis, A., Lehmann, M., & Kadish, A. (2002). Gender differences in arrhythmias. Clinical Cardiology, 25(2), 49–56.
Wysowski, D. K., & Swartz, L. (2005). Adverse drug event surveillance and drug withdrawals in the United States, 1969–2002: the importance of reporting suspected reactions. Archives of Internal Medicine, 165(12), 1363–1369.
Xin, H. B., Senbonmatsu, T., Cheng, D. S., Wang, Y. X., Copello, J. A., Ji, G. J., et al. (2002). Oestrogen protects FKBP12.6 null mice from cardiac hypertrophy. Nature, 416(6878), 334–338.
Acknowledgements
The Center for Gender in Medicine is supported by funding from the Deutsche Froschungsgesellschaft, the Ministry of Education and Research, the Ministry of Family Affairs, Senior Citizens, Women and Youth, and the Margarete Ammond Stiftung.
Conflicts of interest
The authors have no conflicts of interest to declare.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Oertelt-Prigione, S., Regitz-Zagrosek, V. Gender Aspects in Cardiovascular Pharmacology. J. of Cardiovasc. Trans. Res. 2, 258–266 (2009). https://doi.org/10.1007/s12265-009-9114-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12265-009-9114-9