Independent analyses of data from NHANES III and MESA showed that higher levels of free testosterone were associated with shorter QT intervals in men. The association was moderately strong, with average adjusted differences in QT-interval duration of −8.0 ms to −4.7 ms for the highest quartile versus the lowest quartiles of free testosterone in NHANES III and MESA, respectively. No association was found between testosterone level and QT interval in postmenopausal women. At the population level, the association of testosterone with QT-interval duration is substantial and comparable in magnitude to that of common genetic variants that affect QT-interval duration (33
). Differences in testosterone levels could explain differences in QT-interval duration between men and women. Among men, the level of endogenous testosterone could be a key contributor to population variability in QT-interval duration.
Testosterone may shorten QT-interval duration by affecting several repolarizing currents (5, 7−9, 34). In guinea pig myocytes, testosterone at physiologic concentrations induced a dose-dependent shortening of action potential duration through enhancing the slowly activating delayed rectifier current and suppressing the L-type calcium current (5
). Dihydrotestosterone, a metabolite of testosterone, attenuated quinidine-induced QT prolongation in orchiectomized male rabbits, an effect attributed to an increase in the repolorizing inward rectifier current and rapidly activating delayed rectifier current (8
). Finally, in one study, testosterone-treated castrated female dogs and unaltered male dogs had higher expressions of ion channel proteins that underlie inward rectifier current and transient outward current than did estrogen-treated castrated male dogs and unaltered female dogs (7
Few clinical studies have been conducted to evaluate the influence of testosterone on QT-interval duration. A study of 106 patients (27 castrated men, 26 women with virilization, and 53 controls) found that ventricular repolarization was prolonged in castrated men compared with noncastrated men and that women with hyperandrogenism had shorter QT-interval durations than did other women (10
). In another study of 11 hypogonadic men, therapeutic testosterone administration was associated with significant QT-interval shortening (11
). Both studies were relatively small, and their results cannot be extrapolated to the general population. Our findings also confirmed previous findings of 2 smaller cross-sectional analyses from the Rotterdam Study (n
= 445) and the Study of Health in Pomerania (n
= 1,428), in which van Noord et al. (12
) reported an inverse association between total testosterone and the Bazett corrected QT interval. In addition, we showed that free testosterone had a stronger association with the QT interval.
Furthermore, in our analyses, the association between testosterone and QT interval was more prominent in NHANES III men than in the MESA men. This could be due to differences in population characteristics, as NHANES III men were 8 years younger on average and had higher testosterone levels.
Our study found a marginally significant association between estradiol levels and QT-interval duration in postmenopausal women. Experimental data in animals have suggested that estradiol may regulate cardiac repolarization through genomic and nongenomic pathways (6
). In rabbit hearts, estradiol prolonged the duration of the action potential by down-regulating the expression of potassium currents, such as the slowly activating delayed rectifier current (6
). In guinea pig ventricles, estradiol had concentration-dependent effects on cardiac ion channels through nongenomic pathways: At physiologic concentrations, estradiol prolonged QT-interval duration by inhibiting the rapidly activating delayed rectifier current, whereas higher concentrations shortened the QT interval by inhibiting the rapidly activating delayed rectifier current and the L-type calcium current and enhancing the slowly activating delayed rectifier current (13
Studies of estrogen levels and QT intervals in premenopausal women have been inconclusive. During the menstrual cycle, the circulating level of estradiol is lowest at the beginning of the menses, increases in the follicular phase, peaks at ovulation, and then decreases in the luteal phase. Two studies of healthy women (sample sizes of 23 and 21 women) showed no significant differences in QT-interval duration throughout the menstrual cycle (14
), whereas another study of 11 Japanese women showed significantly longer QT intervals in the follicular phase compared with the luteal phase (16
). With respect to hormone replacement therapy in postmenopausal women in a large cross-sectional study from the Women's Health Initiative, Kadish et al. (18
) reported that estrogen-only hormone replacement therapy was associated with a slight but significant prolongation of the QT interval but the combination of estrogen and progestin was associated with a shortening of this interval. In addition, results from the Atherosclerosis Risk in Communities Study showed that estrogen replacement therapy but not progestin plus estrogen replacement therapy was associated with QT-interval prolongation (36
A major strength of our study was the independent replication of the association between testosterone levels and QT-interval duration in men in 2 large general population studies, NHANES III and MESA. Both studies had careful standardization and detailed quality-control procedures that added to the strength of the findings. Because there were methodological differences in sampling procedures, ECG recording, and sex-hormone measurement, we decided not to combine the data; instead, we conducted independent analyses of data from the 2 cohorts separately. The consistency of the findings in both studies supports the validity of the observed inverse association between testosterone levels and QT-interval duration in men.
Several limitations of the present study also need to be considered. QT-interval duration and hormone levels were measured at a single time, which could have resulted in nondifferential measurement error, as there was substantial within-person variability in both exposure and outcome. Our findings suggested that more detailed assessments of both hormone levels and ECG characteristics could further contribute to our understanding of the role of testosterone in QT-interval duration. Another concern is the observational cross-sectional design, which limited our ability to make statements about the causality of the relation between testosterone and QT-interval duration because of potential uncontrolled confounding or selection biases. However, in vitro and experimental animal models have provided a firm experimental basis for the concept of QT shortening by testosterone and support the biologic plausibility of our findings.
In conclusion, data from 2 large general population cohorts showed an inverse association between QT-interval duration and testosterone levels in men but not in women. Testosterone may be a primary determinant of QT-interval duration in men, which could have important implications for understanding sex differences, as well as age-related changes in arrhythmia susceptibility in men. Additional studies in other populations, as well as randomized trials, should be conducted to confirm these findings and to elucidate the clinical impact of sex hormones in modifying the risk of sudden cardiac death and other arrhythmias.