Acute haemodynamic effects of testosterone in men with chronic heart failure

Peter J. Pugha, T. Hugh Jonesb and Kevin S. Channera,*

a Department of Cardiology, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK
b Academic Unit of Endocrinology, Division of Genomic Medicine, University of Sheffield Medical School, Sheffield, UK

* Corresponding author. Tel.: +44-114-271-3473; fax: +44-114-271-2042
E-mail address: kevin.channer{at}sth.nhs.uk

Received 15 October 2002; revised 27 December 2002; accepted 14 January 2003


    Abstract
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims Anabolic therapy with testosterone may be useful in the treatment of wasting associated with chronic heart failure but little is known about its cardiovascular actions. The aim of this study was to determine the acute haemodynamic effects of testosterone administration in men with heart failure.

Methods and results Twelve men with stable chronic heart failure were enrolled in a double-blind, randomised, placebo-controlled, cross-over trial. Subjects were given testosterone 60mg or placebo via the buccal route and central haemodynamics were monitored over 6h, using a pulmonary flotation catheter. Subjects received the second treatment on day 2 and haemodynamic monitoring was repeated. Treatment was well tolerated. Compared with placebo, testosterone treatment resulted in a relative increase in cardiac output (, ANCOVA), with maximum treatment effect after 180min (10.3±4.6% increase from baseline, ; 95% CI 0.8–19.8). This was accompanied by reduction in systemic vascular resistance compared with baseline (, ANCOVA), with maximum treatment effect also at 180min (–17.4±9.6% from baseline, ; 95% CI –37.3 to +2.6). These maximal changes coincided with the peak elevation in serum bio-available testosterone. There was no significant change in any other haemodynamic parameter measured.

Conclusions Administration of testosterone increases cardiac output acutely, apparently via reduction of left ventricular afterload.

Key Words: Heart failure • Haemodynamics • Hormones • Cardiac output


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Chronic heart failure remains a malignant disease, in spite of recent advances in understanding and treatment of the pathological processes. Patients exhibit loss of skeletal muscle bulk and strength, contributing to exercise intolerance. Anabolic treatments have therefore been proposed for improving functional capacity in these patients, and the results of a randomised, controlled trial were recently presented, demonstrating improved exercise capacity and symptoms in men with chronic heart failure following treatment with testosterone (American College of Cardiology, Atlanta, 2002).1 The mechanism of benefit is unclear, however, as no effect on skeletal muscle was observed.

As well as having anabolic properties, testosterone is also known to act as a vasodilator in systemic, coronary and pulmonary vascular beds.2–6 This effect could potentially lead to increased cardiac output and improved cardiovascular function, thereby contributing to the clinical benefit previously observed.

We therefore hypothesised that administration of testosterone to men with chronic congestive heart failure may lead to haemodynamic alterations. The purpose of this study was to determine whether acute administration of testosterone to these patients leads to changes in cardiac output and in left ventricular preload and afterload.


    2. Methods
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
This was a randomised, double-blind, placebo-controlled cross-over trial. The primary outcome measure was cardiac output. Eligible subjects underwent baseline evaluation prior to enrolment. They were asked to complete a questionnaire documenting medical history and current medication. Height and weight were measured. Left ventricular ejection fraction was determined by transthoracic echocardiography.

Blood was taken for measurement of prostate specific antigen. Within 2 weeks of the baseline visit, subjects were admitted to the Royal Hallamshire Hospital for 2 days and underwent right heart catheterisation. On day 1, subjects received treatment with two tablets of testosterone 30mg or identical placebo (both supplied by Columbia Laboratories, Paris, France), administered via the buccal route. The tablets have a specially designed bio-adhesive formulation, allowing them to remain securely in the mouth for long periods, while testosterone is absorbed directly into the circulation, avoiding first pass hepatic metabolism. Haemodynamic parameters and serum hormone levels were measured at baseline and over 6h. At the end of each study period, tablet remnants were removed and each subject rinsed his mouth with water to avoid a carry-over effect. The second drug was administered on day 2 and measurements repeated. Subjects did not eat or drink during each 6h treatment period. Fluids (5% glucose) were given intravenously at a rate of 80mlh–1. Subjects were instructed to stop taking angiotensin converting enzyme inhibitors and angiotensin receptor blockers 72h before admission. Calcium channel blockers, {alpha}-blockers and long acting nitrates were withdrawn 48h before admission. Subjects could continue to use short-acting sub-lingual nitrates up until 6h before admission and continued to take their other medications throughout the study.

2.1. Subjects
Eligible patients were identified from cardiology outpatient clinics and verbally invited to participate. All patients gave written informed consent and the study was approved by the Local Research Ethics Committee. Patients had to be over 18 years with stable chronic heart failure and objective evidence of impaired left ventricular function.

Exclusion criteria were cancer of the prostate or breast, elevated serum level of prostate specific antigen above the normal reference range for age, unable to lie flat for a prolonged period and mental incompetence.

2.2. Assessment
Subjects lay flat in bed in a side room, in calm, quiet conditions. Central venous access was gained via the right subclavian vein and an introducer sheath inserted under local anaesthetic with no additional sedation. A balloon flotation catheter was passed into the pulmonary circulation under fluoroscopic guidance. Initial measurements were performed after at least 90min delay to allow steady state to be established. Cardiac output was measured by thermodilution technique and the mean of three readings was recorded. Measurements were repeated every 15min until there was less than 10% variation between consecutive recordings of cardiac output. When that occurred, measurements at that point were called baseline and the first treatment was given. Haemodynamic measurements were then repeated at , 60, 120, 180, 240, 300 and 360min. Systolic and diastolic blood pressure was measured by an automated sphygmomanometer via an external brachial cuff on the left arm. Mean arterial blood pressure was calculated using the formula: . Systemic vascular resistance was calculated in absolute units (dynscm–5), using the formula: . Pulmonary capillary wedge pressure (PCWP) and pulmonary artery pressure (PAP) were measured directly. Pulmonary vascular resistance (PVR)was calculated in absolute units (dynscm–5), using the formula: . Heart rate was determined by continuous ECG monitoring. Following each measurement, a 12-lead ECG was recorded using a standard electrocardiograph (Marquette Electronics, Milwaukee, USA). Blood was taken via the catheter for measurement of serum sex hormone levels.


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Table 1 Clinical characteristics of subjects and baseline haemodynamic parameters

 


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Fig. 1 Acute changes in bio-available testosterone levels in men with chronic heart failure treated with testosterone and placebo. Normal range >2.5nmoll–1.

 


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Fig. 2 Percent change from baseline of cardiac index (A), heart rate (B), mean arterial blood pressure (C), systemic vascular resistance (D), pulmonary capillary wedge pressure (E), pulmonary artery pressure (F) and pulmonary vascular resistance (G) following buccal administration of testosterone and placebo in 12 men with chronic heart failure. * versus placebo.

 


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Fig. 3 Treatment effect for cardiac index (A) and SVR (B) in subjects with baseline bio-available testosterone above orbelow the median value of 4.57nmoll–1.

 
Serum level of total testosterone was measured by ELISA (DRG Instruments GmbH, Germany). Bio-available testosterone level was measured by the method of Tremblay and Dube.7

2.3. Statistical analysis
Data were analysed by analysis of covariance (ANCOVA), using a general linear model, with treatment, period and time point as fixed factors, subject as random factor and baseline measurement as covariate. The presence of a period effect or treatment–period interaction was initially tested by this method, using the SPSS Statistical Package, version 11.0. Where there was no significant treatment–period interaction or period effect, changes in parameters with each treatment were compared and are presented as % change with time. Where a significant effect of treatment compared with placebo was found, the treatment effect was determined from the change following testosterone treatment minus the change following placebo treatment. The presence of associations between baseline measurements was tested using Spearman's rank correlation (rS). Changes in parameters between treatments at a given time point were compared using the independent samples t test.


    3. Results
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Clinical characteristics of subjects and baseline haemodynamic measurements are shown in Table 1. Eleven were receiving treatment with an angiotensin converting enzyme inhibitor, 10 with diuretics, four with ß-blockers, two with a calcium channel blocker, two with {alpha}-blockers and two with long-acting nitrates. All subjects withdrew from appropriate medications according to the protocol with no adverse effects. Serum levels of bio-available testosterone are shown in Fig. 1. Initial statistical testing showed there to be no significant treatment–period interaction or period effect. There was no significant difference in levels of total and bio-available testosterone between the start of day 1 and day 2 (14.1±7.3 vs 14.1±5.4nmoll–1, ; 4.79±2.26 vs 4.73±2.67nmoll–1, ), nor between the start of active treatment and placebo (14.3±5.9 vs 13.9±6.9nmoll–1, ; 4.61±1.68 vs 4.89±3.12nmoll–1, ). There was a trend to positive correlation between bio-available testosterone level and cardiac index at baseline (, ) but no other association between androgens and haemodynamic measurements.

3.1. Clinical effects
During the study, one subject experienced facial flushing 2h after the end of testosterone treatment. No other subject experienced any adverse event or symptoms attributable to testosterone administration.

3.2. Haemodynamic parameters
Cardiac index fell throughout each study period. This reduction was significantly attenuated by testosterone treatment throughout the study period (Fig. 2A), with maximum treatment effect at 180min (10.3±4.6%, ; 95% CI 0.8–19.8). Throughout the active treatment period, the serum bio-available testosterone level correlated positively with cardiac index (, ). A rise in SVR by almost 25% was markedly attenuated with testosterone treatment (Fig. 2D), with maximum treatment effect also at 180min (–17.4±9.6%, ; 95% CI –37.3 to +2.6). Throughout the active treatment period, there was an inverse relationship between bio-available testosterone level and SVR (, ). There was no significant change in heart rate (Fig. 2B) or mean arterial blood pressure compared with placebo (Fig. 2C).

PCWP tended to increase throughout each study period, with no significant difference between groups (Fig. 2E). There were no significant changes in PAP or in PVR (Fig. 2F and G).

To determine the effect of androgen status on responsiveness to testosterone administration, the effect of treatment on cardiac index and SVR was compared between subjects with baseline bio-available testosterone level either above or below the median value of 4.57nmoll–1. As shown in Fig. 3, the response was significantly greater in subjects with lower endogenous androgens at baseline.


    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
The results of this study show, for the first time, that acute administration of testosterone increases cardiac output compared with placebo. The relative reduction in systemic vascular resistance suggests that the increase in cardiac output is due to arteriolar vasodilatation and reduction of afterload. This is supported by laboratory evidence of a vasodilator effect of testosterone, which is thought to be largely, though not exclusively, due to a calcium channel blocking action at the smooth muscle cell,4,5 mediated by a non-genomic pathway.6,8 Other vasodilator calcium channel blockers have been shown to acutely reduce systemic vascular resistance and increase cardiac output in a similar fashion,9,10 although Walsh et al.11 observed no effect of amlodipine on cardiac output or exercise capacity in 32 patients with chronic heart failure. Tan et al.10 found that treatment with felodipine increased cardiac output in 15 patients with chronic heart failure, with no effect on left ventricular pre-load and no change in exercise capacity. In vitro studies suggest that systemic vessels are highly sensitive to the action of testosterone.2 Coronary arteries appear to be less sensitive, while pulmonary vessels require very high concentrations before responding.5 The findings of the present study are therefore in keeping with previous in vitro work, which would predict a reduction of afterload, with little effect of testosterone on left ventricular preload.

Levels of both total and bio-available testosterone were measured in this study. Only 1–2% of testosterone circulates unbound as free testosterone. However, a further 30% is weakly bound to albumin, from which it freely dissociates. Nearly a third of circulating testosterone is therefore biologically active called bio-available testosterone. The remainder circulates tightly bound to sex hormone binding globulin, and is biologically inactive. Although total testosterone is routinely measured in clinical practice, it is the bio-available fraction which is of greatest clinical importance. The subjects who demonstrated the biggest response to testosterone were those with lowest baseline bio-available testosterone level (normal range >2.5nmoll–1), although only two of 12 subjects had levels below the lower limit of normal. Testosterone may therefore be of benefit in patients with testosterone levels at the lower end of the normal range, as well as those who are frankly hypogonadal. Currently, the proportion of men with chronic heart failure who have reduced testosterone levels is unknown. Whether or not the effects of testosterone administration on cardiac output are responsible for the augmentation of exercise capacity and improvement in symptoms previously observed in men with heart failure is unclear. Certainly, it is recognised that there is a poor relationship between haemodynamic parameters and exercise capacity in chronic heart failure.12 However, it seems likely that the effects observed in the present study at least contribute to the beneficial effects of chronic testosterone therapy.

The reason for the changes in cardiac index and systemic vascular resistance following placebo treatment is not clear but highlight the importance of employing a placebo control in this study, as cardiac index and systemic vascular resistance also fall and rise, respectively, following testosterone treatment. Without observing the changes relative to placebo, the opposite conclusions might have been drawn.

The results of this study are similar to those of Donath et al.,13 who investigated the acute haemodynamic effects of IGF-1 administration in patients with chronic heart failure. In a 2-day, cross-over study, they also found that cardiac output fell throughout each study day, while SVR rose. Intravenous infusion of IGF-1 resulted in a relative increase in cardiac output and stroke volume and reduction in both afterload and preload compared with placebo. The lead investigators suggested that the anabolic and cardiovascular effects of IGF-1 make it an attractive option for the treatment of chronic heart failure,14 although this has yet to be tested. The results of the present study demonstrate the cardiovascular safety of acute administration of testosterone. In conjunction with preliminary reports demonstrating clinical benefit of testosterone treatment in men with heart failure (33% increase in exercise capacity with reduction in symptom scores)1 as well as in men with angina,15–17 these data indicate that the safety and efficacy of testosterone therapy for heart failure require confirmation in a larger, powered trial. Such a study is currently in progress.


    Acknowledgments
 
We thank the Statistical Services Unit of the University of Sheffield for help with design of the study and analysis of the results. This work was funded by a project grant from the National Heart Research Fund (UK). Testosterone and placebo tablets were provided by Columbia Laboratories, Paris, France.


    Footnotes
 
Source of support: National Heart Research Fund (UK) (project grant).


    References
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Pugh PJ, West JN, Jones TH et al. Testosterone therapy improves exercise duration and symptoms in men with chronic congestive heart failure. J Am Coll Cardiol. 2002;39(Suppl):155A.
  2. Tep-areenan P, Kendall DA, Randall MD. Testosterone-induced vasorelaxation in the rat mesenteric arterial bed is predominantly via potassium channels. Br J Pharmacol. 2002;135:735–740.[Abstract/Free Full Text]
  3. English KM, Jones RD, Jones TH et al. Aging reduces the responsiveness of coronary arteries from male Wistar rats to the vasodilatory action of testosterone. Clin Sci. 2000;99:77–82.[Medline]
  4. English KM, Jones RD, Jones TH et al. Testosterone acts asa coronary vasodilator by a calcium antagonistic action. J Endocrinol Invest. 2002;25:455–458.[Medline]
  5. English KM, Jones RD, Jones TH et al. Gender differences in the vasomotor effects of different steroid hormones in rat pulmonary and coronary arteries. Horm Metab Res. 2001;33:1–8.[CrossRef][Medline]
  6. Jones RD, English KM, Pugh PJ et al. The pulmonary vasodilatory action of testosterone—evidence of a calcium antagonistic action. J Cardiovasc Pharmacol. 2002;39:814–823.[CrossRef][Medline]
  7. Tremblay RR, Dube JY. Plasma concentrations of free and non Te-BG bound testosterone in women on oral contraceptives. Contraception. 1974;10:599–605.[Medline]
  8. Yue P, Chatterjee K, Beale C et al. Testosterone relaxes rabbit coronary arteries and aorta. Circulation. 1995;91:1154–1160.[Abstract/Free Full Text]
  9. Vetrovec GW, Plumb V, Epstein AE et al. Evaluation of the acute haemodynamic and electrophysiologic effects of intravenous amlodipine alone and in combination with a betablocker in patients with angina pectoris. J Cardiovasc Pharmacol. 1993;22(Suppl A):S29–S33.
  10. Tan LB, Murray RG, Littler WA. Felodipine in patients with chronic heart failure: discrepant haemodynamic and clinical effects. Br Heart J. 1987;58:122–128.[Abstract]
  11. Walsh JT, Andrews R, Curtis S et al. Effects of amlodipine in patients with chronic heart failure. Am Heart J. 1997;134:872–878.[Medline]
  12. Myers J, Froelicher VF. Hemodynamic determinants of exercise capacity in chronic heart failure. Ann Intern Med. 1991;115:377–386.[Medline]
  13. Donath MY, Sutsch G, Yan X-W et al. Acute cardiovascular effects of insulin-like growth factor in patients with chronic heart failure. J Clin Endocrinol Metab. 1998;83:3177–3183.[Abstract/Free Full Text]
  14. Donath MY, Zapf J. Insulin-like growth factor 1. An attractive option for chronic heart failure? Drugs Aging. 1999;15:251–254.[Medline]
  15. English KM, Steeds RP, Jones TH et al. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomised, double-blind, placebo-controlled study. Circulation. 2000;102:1906–1911.[Abstract/Free Full Text]
  16. Webb CM, Adamson DL, De Zeigler D et al. Effect of acute testosterone on myocardial ischaemia in men with coronary artery disease. Am J Cardiol. 1999;83:437–439.[CrossRef][Medline]
  17. Rosano GMC, Leonardo F, Pagnotta P et al. Acute anti-ischemic effect of testosterone in men with coronary artery disease. Circulation. 1999;99:1666–1670.[Abstract/Free Full Text]