Title: Testosterone encouraging in the elderly with heart failure
August 27, 2009 | Lisa Nainggolan

Rome, Italy - Italian researchers have shown that long-acting testosterone on top of optimal medical therapy seems to improve a range of symptoms in elderly men with chronic heart failure [1]. Dr Giuseppe Caminiti (Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy) and colleagues report their findings in the September 1, 2009 issue of the Journal of the American College of Cardiology.
Those who received testosterone, which was administered as an intramuscular injection, had improved exercise capacity, muscle strength, glucose metabolism, and baroreflex sensitivity (BRS) compared with those who got placebo.
"Our study shows that patients with HF on optimal medical therapy can still benefit from the addition of testosterone therapy, which appeared safe and well tolerated and improved some of the main manifestations of HF," coauthor Dr Ferdinando Iellamo (University of Rome Tor Vergata, Italy) told heartwire.
In an accompanying editorial [2], Norwegian physicians Drs Pål Aukrust and Thor Ueland (Oslo University Hospital) and Drs Lars Gullestad and Arne Yndestad (University of Oslo) discuss prior trials of testosterone in HF and say the study by Caminiti et al "extends these previous findings in several ways." The results of all these trials suggest a move forward to larger studies, they say.

Does testosterone act directly on muscle?
Caminiti et al randomly allocated 70 elderly male patients with CHF to receive, on top of their optimal treatment, either 1000-mg intramuscular-injection long-acting testosterone undecanoate (Nebido, Bayer-Schering), a dose that Iellamo says is similar to that given in hypogonadism, or placebo, at baseline and six and 12 weeks. All patients underwent echocardiogram, cardiopulmonary exercise test, six-minute-walk test, quadriceps maximal voluntary contraction (MVC), isokinetic strength (peak torque), and BRS assessment (sequences technique).
Baseline peak oxygen consumption (VO2) and quadriceps strength (MVC) showed a direct relation with serum testosterone, and both significantly improved in relation to increased testosterone levels in those taking the hormone compared with those on placebo. Insulin sensitivity, peak torque, and BRS were also significantly improved with testosterone compared with placebo. But there were no significant changes in left ventricular (LV) function in either group.
The latter observation suggests that the effects of the hormone appear to be mediated via a direct action on muscle rather than any changes in LV function, Iellamo said. "We have no direct evidence for this," he noted, "but there are animal studies that show that testosterone improves metabolism at the muscular level."
The fact that testosterone improved insulin metabolism, insulin resistance, and glucose metabolism is also important, he notes, because these factors all contribute to a worsening of HF.
And he notes that the intramuscular preparation of testosterone used was well tolerated, with no one withdrawing from the study due to side effects. This is in contrast with previous studies with testosterone patches, in which some patients experienced dermatological problems, causing them to leave the study.

Women with HF seem to benefit from testosterone too
In their editorial, the Norwegian doctors note the novel findings of the study, including the effect of testosterone on insulin sensitivity and muscle. It appears that the hormone is improving static and dynamic muscle performance in larger, weight-bearing muscles, rather than improving LV function by a direct effect on the myocardium, they say. Also, impaired baroreflex activity has been associated with poor prognosis in HF, they point out, and so the improvement in this parameter seen with testosterone suggests "that testosterone deficiency might be involved in the dysregulation of this important axis."
Iellamo said the patients receiving testosterone also improved their NYHA functional class: "There was a subjective 'feeling-better' experience in those who got testosterone, but what is important is that we also observed an improvement in objective measures that carry prognostic importance in HF," he noted.
And although this study was conducted in men, Iellamo says his team has also given the same dose of testosterone to elderly women with heart failure in a preliminary study, with similar results.

Testosterone could be used in those with low levels of the hormone
"At the moment, testosterone is not indicated in current guidelines; we need large multicenter trials before testosterone can be widely used in HF patients," Iellamo said. However, there could be a case for using this therapy in elderly patients who have low testosterone levels, he said. The Norwegian physicians say the results of Caminiti et al suggest "a particularly good response to testosterone therapy" among such patients.
They conclude that the "extracardiac effects" of testosterone "might translate into not only reduced morbidity but also improved myocardial performance and reduced mortality. This aspect should be addressed in forthcoming studies."

Sources

1. Caminiti G, Volterrani M, Iellamo F, et al. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure. A double-blind, placebo-controlled, randomized study. J Am Coll Cardiol 2009; 54:919-927.
2. Aukrust P, Ueland T, Gullestad L, Yndestad A. Testosterone: A novel therapeutic approach in chronic heart failure? Am Coll Cardiol 2009: 54:928-929.

Key points

1. Elderly patients with HF on optimal medical therapy can still benefit from the addition of testosterone therapy
2. They had improved exercise capacity, muscle strength, glucose metabolism, and baroreflex sensitivity (BRS) compared with those who got placebo.
3. The effects of the hormone appear to be mediated via a direct action on muscle rather than any changes in LV function.
4. Testosterone improved insulin metabolism, insulin resistance, and glucose metabolism. This is important because these factors all contribute to a worsening of HF.
5. Conclusion: The "extracardiac effects" of testosterone "might translate into not only reduced morbidity but also improved myocardial performance and reduced mortality