Advertisement

Dihydrotestosterone—a culprit in left ventricular hypertrophy

Published:January 24, 2012DOI:https://doi.org/10.1016/j.ijcard.2011.12.037
      Independent clinical studies have demonstrated a relationship between testosterone and cardiac mass with Hayward et al. being the first to report the idea that sex hormones are involved in cardiac hypertrophy [
      • Hayward C.S.
      • Webb C.M.
      • Collins P.
      Effect of sex hormones on cardiac mass.
      ]. There is clear evidence to suggest testosterone to induce cardiac hypertrophy and left ventricular hypertrophy which is an important risk factor for cardiovascular morbidity and mortality [
      • Hayward C.S.
      • Webb C.M.
      • Collins P.
      Effect of sex hormones on cardiac mass.
      ]. Indeed, the male heart is hypertrophied relative to the premenopausal female heart, even when corrected for body weight [
      • Marsh J.D.
      • Lehmann M.H.
      • Ritchie R.H.
      • Gwathmey J.K.
      • Green G.E.
      • Schiebinger R.J.
      Androgen receptors mediate hypertrophy in cardiac myocytes.
      ,
      • MacLean H.E.
      • Moore A.J.
      • Sastra S.A.
      • et al.
      DNA-binding-dependent androgen receptor signaling contributes to gender differences and has physiological actions in males and females.
      ]. However, with age, ventricular mass increases in women but remains constant or rather decreases in men [
      • Dannenberg A.L.
      • Levy D.
      • Garrison R.J.
      Impact of age on echocardiographic left ventricular mass in a healthy population (the Framingham Study).
      ,
      • Olivetti G.
      • Giordano G.
      • Corradi D.
      • et al.
      Gender differences and aging: effects on the human heart.
      ]. Thus, in recent years the role of androgens on cardiac mass and function has become the subject of intensive research. The exact role of androgens in cardiac physiology is still not fully understood. However, preclinical and clinical findings suggest testosterone supplementation at supraphysiological concentrations to be associated with structural and morphological changes of the heart, resulting in an increased cardiovascular morbidity and mortality [
      • Achar S.
      • Rostamian A.
      • Narayan S.M.
      Cardiac and metabolic effects of anabolic-androgenic steroid abuse on lipids, blood pressure, left ventricular dimensions, and rhythm.
      ]. Conversely, androgen deficiency is also linked to cardiovascular mortality, therefore suggesting that a fine balance in testosterone cardiac tissue levels exists with low levels of testosterone being a risk factor for cardiovascular events [
      • Bassil N.
      • Alkaade S.
      • Morley J.E.
      The benefits and risks of testosterone replacement therapy: a review.
      ,
      • Malkin C.J.
      • Pugh P.J.
      • Morris P.D.
      • Asif S.
      • Jones T.H.
      • Channer K.S.
      Low serum testosterone and increased mortality in men with coronary heart disease.
      ]. Importantly, testosterone metabolism is significantly changed in left ventricular hypertrophy with levels of metabolites like androstendione and dihydrotestosterone being increased [
      • Thum T.
      • Borlak J.
      Testosterone, cytochrome P450, and cardiac hypertrophy.
      ]. These changes return to normal by adding finasteride, a 5α-reductase inhibitor to cultures of cardiomyocytes isolated from hypertrophic hearts of spontaneously hypertensive rats (SHR). Furthermore, in experimental studies, addition of testosterone reduced expression of the stress marker atrial natriuretic peptide (ANP) and improved expression of cardiomyocyte differentiation markers, e.g. the homeodomain protein Nkx 2·5 and the zinc-finger protein GATA4 both of which function as transcription factors in the control of gene expression as well as α-myosin heavy chain (α-MHC) [
      • Borlak J.
      • Thum T.
      Hallmarks of ion channel gene expression in end-stage heart failure.
      ]. These results suggest that testosterone at certain concentrations maintains physiologic cardiac morphology and function while abnormal testosterone levels in either way seem to result in cardiac impairment. Here we present evidence whereby metabolism of testosterone in hypertrophic myocardium leads to exaggerated levels of dihydrotestosterone and we hypothesize that unlike testosterone itself dihydrotestosterone plays an essential role in mediating responses to exacerbate pathologic left ventricular hypertrophy. Moreover, we postulate that reduction of dihydrotestosterone production via inhibition of the 5α-reductase protects the heart, at least in part, from pathologic remodeling.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to International Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Hayward C.S.
        • Webb C.M.
        • Collins P.
        Effect of sex hormones on cardiac mass.
        Lancet. 2001; 357: 1354-1356
        • Marsh J.D.
        • Lehmann M.H.
        • Ritchie R.H.
        • Gwathmey J.K.
        • Green G.E.
        • Schiebinger R.J.
        Androgen receptors mediate hypertrophy in cardiac myocytes.
        Circulation. 1998; 98: 256-261
        • MacLean H.E.
        • Moore A.J.
        • Sastra S.A.
        • et al.
        DNA-binding-dependent androgen receptor signaling contributes to gender differences and has physiological actions in males and females.
        J Endocrinol. 2010; 206: 93-103
        • Dannenberg A.L.
        • Levy D.
        • Garrison R.J.
        Impact of age on echocardiographic left ventricular mass in a healthy population (the Framingham Study).
        Am J Cardiol. 1989; 64: 1066-1068
        • Olivetti G.
        • Giordano G.
        • Corradi D.
        • et al.
        Gender differences and aging: effects on the human heart.
        J Am Coll Cardiol. 1995; 26: 1068-1079
        • Achar S.
        • Rostamian A.
        • Narayan S.M.
        Cardiac and metabolic effects of anabolic-androgenic steroid abuse on lipids, blood pressure, left ventricular dimensions, and rhythm.
        Am J Cardiol. 2010; 106: 893-901
        • Bassil N.
        • Alkaade S.
        • Morley J.E.
        The benefits and risks of testosterone replacement therapy: a review.
        Ther Clin Risk Manage. 2009; 5: 427-448
        • Malkin C.J.
        • Pugh P.J.
        • Morris P.D.
        • Asif S.
        • Jones T.H.
        • Channer K.S.
        Low serum testosterone and increased mortality in men with coronary heart disease.
        Heart. 2010; 96: 1821-1825
        • Thum T.
        • Borlak J.
        Testosterone, cytochrome P450, and cardiac hypertrophy.
        FASEB J. 2002; 16: 1537-1549
        • Borlak J.
        • Thum T.
        Hallmarks of ion channel gene expression in end-stage heart failure.
        FASEB J. 2003; 17: 1592-1608
        • Regitz-Zagrosek V.
        • Oertelt-Prigione S.
        • Seeland U.
        • Hetzer R.
        Sex and gender differences in myocardial hypertrophy and heart failure.
        Circ J. 2010; 74: 1265-1273
        • Hayward C.S.
        • Kelly R.P.
        • Collins P.
        The roles of gender, the menopause and hormone replacement on cardiovascular function.
        Cardiovasc Res. 2000; 46: 28-49
        • Baltatu O.
        • Cayla C.
        • Iliescu R.
        • Andreev D.
        • Bader M.
        Abolition of end-organ damage by antiandrogen treatment in female hypertensive transgenic rats.
        Hypertension. 2003; 41: 830-833
        • Pirgon O.
        • Atabek M.E.
        • Oran B.
        • Suleymanoglu S.
        • Meral C.
        Treatment with human chorionic gonadotropin induces left ventricular mass in cryptorchid boys.
        J Pediatr Endocrinol Metab. 2009; 22: 449-454
        • Vanberg P.
        • Atar D.
        Androgenic anabolic steroid abuse and the cardiovascular system.
        Handb Exp Pharmacol. 2010; : 411-457
        • Rocha F.L.
        • Carmo E.C.
        • Roque F.R.
        • et al.
        Anabolic steroids induce cardiac renin–angiotensin system and impair the beneficial effects of aerobic training in rats.
        Am J Physiol Heart Circ Physiol. 2007; 293: H3575-H3583
        • Liu P.Y.
        • Death A.K.
        • Handelsman D.J.
        Androgens and cardiovascular disease.
        Endocr Rev. 2003; 24: 313-340
        • Svartberg J.
        • von M.D.
        • Schirmer H.
        • Barrett-Connor E.
        • Sundfjord J.
        • Jorde R.
        Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromso Study.
        Eur J Endocrinol. 2004; 150: 65-71
        • Malkin C.J.
        • Pugh P.J.
        • Morris P.D.
        • et al.
        Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life.
        Heart. 2004; 90: 871-876
        • Mathur A.
        • Malkin C.
        • Saeed B.
        • Muthusamy R.
        • Jones T.H.
        • Channer K.
        Long-term benefits of testosterone replacement therapy on angina threshold and atheroma in men.
        Eur J Endocrinol. 2009; 161: 443-449
        • Yeap B.B.
        Androgens and cardiovascular disease.
        Curr Opin Endocrinol Diabetes Obes. 2010; 17: 269-276
        • Phillips G.B.
        • Pinkernell B.H.
        • Jing T.Y.
        The association of hypotestosteronemia with coronary artery disease in men.
        Arterioscler Thromb. 1994; 14: 701-706
        • Cavasin M.A.
        • Sankey S.S.
        • Yu A.L.
        • Menon S.
        • Yang X.P.
        Estrogen and testosterone have opposing effects on chronic cardiac remodeling and function in mice with myocardial infarction.
        Am J Physiol Heart Circ Physiol. 2003; 284: H1560-H1569
        • Souverein P.C.
        • Herings R.M.
        • Man in 't Veld A.J.
        • de la Rosette J.J.
        • Farmer R.D.
        • Leufkens H.G.
        Study of the association between ischemic heart disease and use of alpha-blockers and finasteride indicated for the treatment of benign prostatic hyperplasia.
        Eur Urol. 2002; 42: 254-261
      1. Weismann KM and Goldberg M; Therapeutic uses of finasteride. US patent 6090409.

        • Deslypere J.P.
        • Young M.
        • Wilson J.D.
        • McPhaul M.J.
        Testosterone and 5 alpha-dihydrotestosterone interact differently with the androgen receptor to enhance transcription of the MMTV-CAT reporter gene.
        Mol Cell Endocrinol. 1992; 88: 15-22
        • Hsiao P.W.
        • Thin T.H.
        • Lin D.L.
        • Chang C.
        Differential regulation of testosterone vs. 5alpha-dihydrotestosterone by selective androgen response elements.
        Mol Cell Biochem. 2000; 206: 169-175