Download PDF
Horm Metab Res
DOI: 10.1055/a-2569-7387
Original Article: Endocrine Research

Testosterone Depriviation Impairs Cardiac Systolic Function in Orchiectomized Wistar Rats

Gabriela Almeida Motta
1   Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Brazil
,
Graziele Halmenschlager
1   Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Brazil
4   Universidade La Salle, Canoas, Brazil
,
Rachel Pinto Dornelles Dutra
1   Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Brazil
,
Cláudia Ramos Rhoden
1   Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Brazil
,
Ângela Maria Vicente Tavares
2   Fisiologia, UFRGS, Porto Alegre, Brazil
5   Atitus Educação, Passo Fundo, Brazil
,
Alexandre Luz de Castro
2   Fisiologia, UFRGS, Porto Alegre, Brazil
,
Alex Sander da Rosa Araujo
2   Fisiologia, UFRGS, Porto Alegre, Brazil
,
Adriane Belló-Klein
2   Fisiologia, UFRGS, Porto Alegre, Brazil
,
Karen Breitenbach da Silva
1   Biociências, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Brazil
,
Ernani Luis Rhoden
3   Urology, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Brazil
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

Several studies have linked low levels of testosterone with increased symptoms of cardiac disease and cardiovascular mortality; however, the effects of testosterone deficiency on cardiac systolic function and morphology are still not completely elucidated. The present study aims to evaluate the influence of testosterone deprivation on cardiac systolic function and morphology. Male Wistar rats were divided into two groups: Sham operation group (Sham): animals underwent sham operation and Orchiectomized group (Orchiec): animals underwent bilateral orchiectomy. The experimental protocol lasted 60 days after the surgery. All animals were weighted and blood samples collected to serum testosterone analysis, determined by chemiluminescence, on first (before orchiectomy) and on 60th days. One day before euthanasia (on the 59th day) echocardiographic parameters were assessed to evaluate left ventricle (LV) systolic function and morphology. Statistical significant difference was set at≤0.05. Orchiec rats presented reduced LV fractional shortening (p=0.032), increased myocardial performance index (MPI) (p=0.043), prolonged mitral valve closure time (p=0.013) and decreased heart rate (p=0.049) when compared to Sham. No statistically significant difference was found in the ejection fraction (p=0.666) between groups. Besides that, heart weight was lower in Orchiec group (p=0.035) when compared to Sham group. Testosterone deprivation reduced cardiac systolic function, changing contraction and relaxation parameters. Testosterone deficiency also changed heart rate and heart weight. The present study demonstrated for the first time that castrated levels of testosterone could alter parameters such as mitral valve closing time and MPI.

Keywords

testosterone deprivation - echocardiography - cardiac systolic function


Publication History

Received: 17 November 2024

Accepted after revision: 24 March 2025

Article published online:
22 April 2025

© 2025. Thieme. All rights reserved.

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

 

  • References

  • 1 Traish AM. Adverse health effects of testosterone deficiency (TD) in men. Steroids 2014; 88: 106-116
    PubMedSearch in Google Scholar
  • 2 Gagliano-Jucá T, Basaria S. Testosterone replacement therapy and cardiovascular risk. Nat Rev Cardiol 2019; 16: 555-574
    CrossrefPubMedSearch in Google Scholar
  • 3 Basaria S, Coviello AD, Travison TG. et al. Adverse events associated with testosterone administration. N Engl J Med 2010; 363: 109-122
    CrossrefPubMedSearch in Google Scholar
  • 4 Alkamel A, Shafiee A, Jalali A. et al. The association between premature coronary artery disease and level of testosterone in young adult males. Arch Iran Med 2014; 17: 545-550
    PubMedSearch in Google Scholar
  • 5 Basaria S, Harman SM, Travison TG. et al. Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial. JAMA 2015; 314: 570-581
    PubMedSearch in Google Scholar
  • 6 Zeller T, Appelbaum S, Kuulasmaa K. et al. Predictive value of low testosterone concentrations regarding coronary heart disease and mortality in men and women - evidence from the FINRISK97 study. J Intern Med 2019; 286: 317-325
    PubMedSearch in Google Scholar
  • 7 Araujo AB, Kupelian V, Page ST. et al. Sex steroids and all-cause and cause-specific mortality in men. Arch Intern Med 2007; 167: 1252-1260
    PubMedSearch in Google Scholar
  • 8 Fode M, Salonia A, Minhas S. et al. Late-onset hypogonadism and testosterone therapy – a summary of guidelines from the American urological association and the European association of urology. Eur Urol Focus 2019; 5: 539-544
    CrossrefPubMedSearch in Google Scholar
  • 9 Lincoff AM, Bhasin S, Flevaris P. et al. TRAVERSE study investigators. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med 2023; 389: 107-117
    CrossrefPubMedSearch in Google Scholar
  • 10 Windfeld-Mathiasen J, Heerfordt IM, Dalhoff KP. et al. Mortality among users of anabolic steroids. JAMA 2024; 331: 1229-1230
    PubMedSearch in Google Scholar
  • 11 Hu JR, Duncan MS, Morgans AK. et al. Cardiovascular effects of androgen deprivation therapy in prostate cancer: contemporary Meta-analyses. Arterioscler Thromb Vasc Biol 2020; 40: e55-e64
    PubMedSearch in Google Scholar
  • 12 Dalpiaz PL, Lamas AZ, Caliman IF. et al. Sex hormones promote opposite effects on ACE and ACE2 activity, hypertrophy and cardiac contractility in spontaneously hypertensive rats. PLoS One 2015; 10: e0127515
    CrossrefPubMedSearch in Google Scholar
  • 13 Tsai WC, Yang LY, Chen YC. et al. Ablation of the androgen receptor gene modulates atrial electrophysiology and arrhythmogenesis with calcium protein dysregulation. Endocrinology 2013; 154: 2833-2842
    PubMedSearch in Google Scholar
  • 14 Golden KL, Marsh JD, Jiang Y. Castration reduces mRNA levels for calcium regulatory proteins in rat heart. Endocrine 2002; 19: 339-344
    PubMedSearch in Google Scholar
  • 15 Tsang S, Wong SS, Wu S. et al. Testosterone-augmented contractile responses to alpha1- and beta1-adrenoceptor stimulation are associated with increased activities of RyR, SERCA, and NCX in the heart. Am J Physiol Cell Physiol 2009; 296: C766-C782
    PubMedSearch in Google Scholar
  • 16 Witayavanitkul N, Woranush W, Bupha-Intr T. et al. Testosterone regulates cardiac contractile activation by modulating SERCA but not NCX activity. Am J Physiol Heart Circ Physiol 2013; 304: H465-H472
    PubMedSearch in Google Scholar
  • 17 Hsu JC, Cheng CC, Kao YH. et al. Testosterone regulates cardiac calcium homeostasis with enhanced ryanodine receptor 2 expression through activation of TGF-β. Int J Cardiol 2015; 190: 11-14
    PubMedSearch in Google Scholar
  • 18 Sebag IA, Gillis MA, Calderone A. et al. Sex hormone control of left ventricular structure/function: mechanistic insights using echocardiography, expression, and DNA methylation analyses in adult mice. Am J Physiol Heart Circ Physiol 2011; 301: H1706-H1715
    PubMedSearch in Google Scholar
  • 19 Salem JE, Alexandre J, Bachelot A. et al. Influence of steroid hormones on ventricular repolarization. Pharmacol Ther 2016; 167: 38-47
    PubMedSearch in Google Scholar
  • 20 Malkin CJ, Pugh PJ, Jones RD. et al. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab 2004; 89: 3313-3318
    CrossrefPubMedSearch in Google Scholar
  • 21 Pongkan W, Chattipakorn SC, Chattipakorn N. Chronic testosterone replacement exerts cardioprotection against cardiac ischemia-reperfusion injury by attenuating mitochondrial dysfunction in testosterone-deprived rats. PLoS One 2015; 10: e0122503
    PubMedSearch in Google Scholar
  • 22 Eleawa SM, Sakr HF, Hussein AM. et al. Effect of testosterone replacement therapy on cardiac performance and oxidative stress in orchidectomized rats. Acta Physiol (Oxf) 2013; 209: 136-147
    PubMedSearch in Google Scholar
  • 23 Ayaz O, Banga S, Heinze-Milne S. et al. Long-term testosterone deficiency modifies myofilament and calcium-handling proteins and promotes diastolic dysfunction in the aging mouse heart. Am J Physiol Heart Circ Physiol 2019; 316: H768-H780
    PubMedSearch in Google Scholar
  • 24 Kanar BG, Ozben B, Sunbul M. et al. Androgen-deprivation therapy impairs left ventricle functions in prostate cancer patients. Int Urol Nephrol 2019; 51: 1107-1112
    PubMedSearch in Google Scholar
  • 25 Hydock DS, Wonders KY, Schneider CM. et al. Androgen deprivation therapy and cardiac function: effects of endurance training. Prostate Cancer Prostatic Dis 2006; 9: 392-398
    PubMedSearch in Google Scholar
  • 26 National Research Council. 2011. Guide for the Care and Use of Laboratory Animals: Eighth Edition. Washington, DC: The National Academies Press. https://doi.org/10.17226/12910
    CrossrefPubMed
  • 27 Tavares AM, da Rosa Araujo AS, Llesuy S. et al. Early loss of cardiac function in acute myocardial infarction is associated with redox imbalance. Exp Clin Cardiol 2012; 17: 263-267
    PubMedSearch in Google Scholar
  • 28 Gottdiener JS, Bednarz J, Devereux R. et al. American society of echocardiography. American society of echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr 2004; 17: 1086-1119
    PubMedSearch in Google Scholar
  • 29 de Castro AL, Tavares AV, Fernandes RO. et al. T3 and T4 decrease ROS levels and increase endothelial nitric oxide synthase expression in the myocardium of infarcted rats. Mol Cell Biochem 2015; 408: 235-243
    PubMedSearch in Google Scholar
  • 30 Weerateerangkul P, Shinlapawittayatorn K, Palee S. et al. Early testosterone replacement attenuates intracellular calcium dyshomeostasis in the heart of testosterone-deprived male rats. Cell Calcium 2017; 67: 22-30
    PubMedSearch in Google Scholar
  • 31 Gottdiener JS, Bednarz J, Devereux R. et al. A report from the American society of echocardiography’s guidelines and standards committee and the task force on echocardiography in clinical trials. J Am Soc Echocardiogr 2004; 17: 1086-1119
    PubMedSearch in Google Scholar
  • 32 Hussein MF, Al-Mayahi SR, Essa SI. The role of myocardial performance index in assessment of left ventricular function in patients with valvular mitral regurgitation. Int J Cardiol 2017; 230: 25-27
    PubMedSearch in Google Scholar
  • 33 Uemura K, Kawada T, Zheng C. et al. Myocardial performance index is sensitive to changes in cardiac contractility, but is also affected by vascular load condition. Annu Int Conf IEEE Eng Med Biol Soc 2013; 695-698
    PubMedSearch in Google Scholar
  • 34 Cury AF, Bonilha A, Saraiva R. et al. Myocardial performance index in female rats with myocardial infarction: relationship with ventricular function parameters by Doppler echocardiography. J Am Soc Echocardiogr 2005; 18: 454-460
    PubMedSearch in Google Scholar
  • 35 Dujardin KS, Tei C, Yeo TC. et al. Prognostic value of a Doppler index combining systolic and diastolic performance in idiopathic-dilated cardiomyopathy. Am J Cardiol 1998; 82: 1071-1076
    PubMedSearch in Google Scholar
  • 36 Tei C, Ling LH, Hodge DO. et al. New index of combined systolic and diastolic myocardial performance: a simple and reproducible measure of cardiac function- a study in normals and dilated cardiomyopathy. J Cardiol 1995; 26: 357-366
    PubMedSearch in Google Scholar
  • 37 Harjai KJ, Scoott L, Vivekananthan K. et al. The Tei index: a new prognostic index for patients with symptomatic heart failure. J Am Soc Echocardiogr 2002; 15: 864-868
    PubMedSearch in Google Scholar
  • 38 Parthenakis FI, Kanakaraki MK, Kanoupakis EM. et al. Value of Doppler index combining systolic and diastolic miocardial performance in predicting cardiopulmonary exercise capacity in pacients with congestive heart failure: coll effects of dobutamine. Chest 2002; 121: 1935-1941
    PubMedSearch in Google Scholar
  • 39 De Silva NL, Papanikolaou N, Grossmann M. et al. Male hypogonadism: pathogenesis, diagnosis, and management. Lancet Diabetes Endocrinol 2024; 12: 761-774
    PubMedSearch in Google Scholar
  • 40 Babcock MC, DuBose LE, Hildreth KL. et al. Age-associated reductions in cardiovagal baroreflex sensitivity are exaggerated in middle-aged and older men with low testosterone. J Appl Physiol (1985) 2022; 133: 403-415
    PubMedSearch in Google Scholar
  • 41 Basaria S, Coviello AD, Travison TG. et al. Adverse events associated with testosterone administration. N Engl J Med 2010; 363: 109-122
    CrossrefPubMedSearch in Google Scholar