Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes

Torsades de pointes (TdP) is a potentially fatal ventricular arrhythmia associated with
corrected QT (QTc) interval prolongation. More than 50 commonly used drugs available on the
US market may cause QTc interval prolongation and TdP. While TdP occurs more commonly in
women, 33-45% of all cases of TdP have occurred in men. Older age is a risk factor for
drug-induced TdP in men, possibly due to declining serum testosterone concentrations.
Available evidence shows an inverse relationship between QTc intervals and serum testosterone
concentrations. In addition, experimental data, including those from the investigators'
laboratory, suggest that both exogenous testosterone or progesterone administration may be
protective against prolongation of ventricular repolarization and TdP. Specific Aim:
Establish the influence of transdermal testosterone administration and oral progesterone
administration as preventive methods by which to diminish the degree of drug-induced QT
interval prolongation in men 65 years of age or older. Hypothesis: Transdermal testosterone
administration and oral progesterone administration both effectively attenuate drug-induced
QT interval response in older men. To test this hypothesis, transdermal testosterone, oral
progesterone or placebo will be administered in a 3-way crossover study to men 65 years of
age or older. QTc interval response to low-dose ibutilide will be assessed. The primary
endpoints will be Fridericia-corrected QT interval (QTF) response to ibutilide, in the
presence and absence of testosterone, and in the presence or absence of progesterone: 1)
Effect on pre-ibutilide QTF, 2) Effect on maximum post-ibutilide QTF, 3) Effect on % change
in post-ibutilide QTF, and 2) Area under the QTF interval-time curves.