Gender disparity in cardiac electrophysiology: implications for cardiac safety pharmacology

Gender differences in cardiac electrophysiology were reported for the first time almost a century ago. The importance for safety pharmacology became significant when modern medicine came into use and women appeared to be more susceptible to drug-induced Torsade de Pointes (TdP). To unravel the underlying mechanisms, the effect of sex hormones on cardiac electrophysiology has been studied in humans, animals and cell models. In this review, these data have been summarized and discussed in regard to possible consequences for safety pharmacology testing.

In man, electrophysiological differences become apparent during adolescence when the QTc interval shortens in males. This protective effect for long-QT related arrhythmias can be correlated to testosterone levels. Testosterone likely suppresses I(Ca,L) and enhances I(K) which increases the repolarization reserve. Though progesterone may have similar effects in women, these effects are probably balanced out by the small but opposite effects of estrogen. Progesterone levels, however, vary importantly throughout the different phases of the human menstrual cycle, implying that the sensitivity for drug-induced TdP changes too. The consequences for drug safety testing and TdP have not been assessed.

The testosterone-mediated increase in repolarization reserve in men is a likely cause for their lower susceptibility to drug-induced TdP. For the female population, the shifting balance in estrogen and progesterone creates temporal variation in the lability of repolarization to drug-induced TdP. This is a possible confounding factor in the evaluation and comparison of drugs that has to be further tested.