madman
Super Moderator
ABSTRACT
We have previously reported that transdermal testosterone attenuates drug-induced QT interval lengthening in older men. However, it is unknown whether this is due to the modulation of early ventricular repolarization, late repolarization, or both. In a secondary analysis of a prospective, randomized, double-blind, placebo-controlled three-way crossover study, we determined if transdermal testosterone and oral progesterone attenuate drug-induced lengthening of early and late ventricular repolarization, represented by the electrocardiographic measurements J-Tpeakc and Tpeak-Tend, respectively, as well as Tpeak-Tend/QT, a measure of transmural dispersion of repolarization. Male volunteers ≥ 65 years of age (n=14) were randomized to receive transdermal testosterone 100 mg, oral progesterone 400 mg, or matching transdermal/oral placebo daily for 7 days. On the morning following the 7th day, subjects received intravenous ibutilide 0.003 mg/kg, after which ECGs were performed serially. One subject was excluded due to difficulty in T-wave interpretation. Pre-ibutilide J-Tpeakc was lower during the testosterone phase than during progesterone and placebo (216 ± 23 vs 227 ± 28 vs 227 ± 21 ms, p=0.002). Maximum post-ibutilide J-Tpeakc was also lower during the testosterone phase (233 ± 22 vs 246 ± 29 vs 248 ± 23 ms, p<0.0001). Pre-ibutilide Tpeak-Tend was not significantly different during the three phases, but the maximum post-ibutilide Tpeak-Tend was lower during the testosterone phase (80 ± 12 vs 89 ± 18 vs 86 ± 15 ms, p=0.002). Maximum Tpeak-Tend/QT was also lower during the testosterone phase (0.199 ± 0.023 vs 0.216 ± 0.035 vs 0.209 ± 0.031, p=0.005). Progesterone exerted a minimal effect on the drug-induced lengthening of J-Tpeakc, and no effect on TpeakTend or Tpeak-Tend/QT. Transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular repolarization in older men.
INTRODUCTION
QT interval prolongation portends an increased risk of torsades de pointes (TdP), which can cause sudden cardiac death.1 Older age is a risk factor,2,3 which, in men, may be attributable to declining serum testosterone concentrations.4 Testosterone and the androgenic female sex hormone progesterone have been shown in preclinical studies to protect against the drug-induced prolongation of ventricular repolarization5,6 and arrhythmias.7,8 In a randomized, double-blind, placebo-controlled crossover-design proof-of-concept study, we found that transdermal testosterone attenuates drug-induced QT lengthening in men ≥65 years of age.9 The influence of oral progesterone on drug-induced QT lengthening was minimal.
In conclusion, transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular repolarization in older men and may attenuate drug-induced increases in global TDR. These findings suggest that transdermal testosterone may be effective for the attenuation of QT prolongation provoked by drugs that lengthen early repolarization, late repolarization, or both.
STUDY HIGHLIGHTS
What is the Current Knowledge on This Topic?
Transdermal testosterone attenuates drug-induced QT interval lengthening in men ≥65 years of age. However, it is unknown whether transdermal testosterone or the androgenic female sex hormone progesterone attenuates drug-induced lengthening of early versus late ventricular repolarization.
What Question Did This Study Address?
We determined the effects of transdermal testosterone and oral progesterone on the drug-induced lengthening of early and late ventricular repolarization, represented by the J-Tpeakc and Tpeak–Tend intervals, respectively, and increases in transmural dispersion of repolarization (TDR), represented by Tpeak-Tend and Tpeak-Tend/QT.
What Does This Study Add to Our Knowledge?
Transdermal testosterone attenuated drug-induced lengthening of J-Tpeakc, Tpeak-Tend and increases in Tpeak-Tend/QT interval. Oral progesterone exerted minimal effects.
How Might This Change Clinical Pharmacology or Translational Science?
Transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular repolarization in older men and may attenuate increases in global TDR. This suggests that transdermal testosterone may be effective for the attenuation of QT prolongation provoked by drugs that lengthen early repolarization, late repolarization, or both, and has the potential to modify proarrhythmic risk.
We have previously reported that transdermal testosterone attenuates drug-induced QT interval lengthening in older men. However, it is unknown whether this is due to the modulation of early ventricular repolarization, late repolarization, or both. In a secondary analysis of a prospective, randomized, double-blind, placebo-controlled three-way crossover study, we determined if transdermal testosterone and oral progesterone attenuate drug-induced lengthening of early and late ventricular repolarization, represented by the electrocardiographic measurements J-Tpeakc and Tpeak-Tend, respectively, as well as Tpeak-Tend/QT, a measure of transmural dispersion of repolarization. Male volunteers ≥ 65 years of age (n=14) were randomized to receive transdermal testosterone 100 mg, oral progesterone 400 mg, or matching transdermal/oral placebo daily for 7 days. On the morning following the 7th day, subjects received intravenous ibutilide 0.003 mg/kg, after which ECGs were performed serially. One subject was excluded due to difficulty in T-wave interpretation. Pre-ibutilide J-Tpeakc was lower during the testosterone phase than during progesterone and placebo (216 ± 23 vs 227 ± 28 vs 227 ± 21 ms, p=0.002). Maximum post-ibutilide J-Tpeakc was also lower during the testosterone phase (233 ± 22 vs 246 ± 29 vs 248 ± 23 ms, p<0.0001). Pre-ibutilide Tpeak-Tend was not significantly different during the three phases, but the maximum post-ibutilide Tpeak-Tend was lower during the testosterone phase (80 ± 12 vs 89 ± 18 vs 86 ± 15 ms, p=0.002). Maximum Tpeak-Tend/QT was also lower during the testosterone phase (0.199 ± 0.023 vs 0.216 ± 0.035 vs 0.209 ± 0.031, p=0.005). Progesterone exerted a minimal effect on the drug-induced lengthening of J-Tpeakc, and no effect on TpeakTend or Tpeak-Tend/QT. Transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular repolarization in older men.
INTRODUCTION
QT interval prolongation portends an increased risk of torsades de pointes (TdP), which can cause sudden cardiac death.1 Older age is a risk factor,2,3 which, in men, may be attributable to declining serum testosterone concentrations.4 Testosterone and the androgenic female sex hormone progesterone have been shown in preclinical studies to protect against the drug-induced prolongation of ventricular repolarization5,6 and arrhythmias.7,8 In a randomized, double-blind, placebo-controlled crossover-design proof-of-concept study, we found that transdermal testosterone attenuates drug-induced QT lengthening in men ≥65 years of age.9 The influence of oral progesterone on drug-induced QT lengthening was minimal.
In conclusion, transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular repolarization in older men and may attenuate drug-induced increases in global TDR. These findings suggest that transdermal testosterone may be effective for the attenuation of QT prolongation provoked by drugs that lengthen early repolarization, late repolarization, or both.
STUDY HIGHLIGHTS
What is the Current Knowledge on This Topic?
Transdermal testosterone attenuates drug-induced QT interval lengthening in men ≥65 years of age. However, it is unknown whether transdermal testosterone or the androgenic female sex hormone progesterone attenuates drug-induced lengthening of early versus late ventricular repolarization.
What Question Did This Study Address?
We determined the effects of transdermal testosterone and oral progesterone on the drug-induced lengthening of early and late ventricular repolarization, represented by the J-Tpeakc and Tpeak–Tend intervals, respectively, and increases in transmural dispersion of repolarization (TDR), represented by Tpeak-Tend and Tpeak-Tend/QT.
What Does This Study Add to Our Knowledge?
Transdermal testosterone attenuated drug-induced lengthening of J-Tpeakc, Tpeak-Tend and increases in Tpeak-Tend/QT interval. Oral progesterone exerted minimal effects.
How Might This Change Clinical Pharmacology or Translational Science?
Transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular repolarization in older men and may attenuate increases in global TDR. This suggests that transdermal testosterone may be effective for the attenuation of QT prolongation provoked by drugs that lengthen early repolarization, late repolarization, or both, and has the potential to modify proarrhythmic risk.
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