Julia Donner, MD (’23)
Pediatric Cardiology Elective
Prolongation of QT interval carries increased risk for sudden life threatening arrythmias, specifically torsades de pointes (TdP) and sudden cardiac death (SCD). Female gender is a risk factor for arrythmias, specifically drug related TdP, and both endogenous and exogenous sex hormones affect the QT interval. The impact of gender and gonadal steroids on cardiac rhythm and arrhythmias is recognized and is more prominent in females than in males. There is a higher propensity towards arrhythmia in females than males and rate corrected QT intervals are longer in females than males. While QTc intervals are longer in women than in men, this difference only becomes apparent after puberty suggesting that sex hormones may be responsible. In addition, progesterone, not estrogen has dominant effect on ventricular repolarization in women. Androgens are known to be protective and higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening.
The way in which sex hormones modulate QT is through delayed rectifier potassium channels. In animal and human studies estrogen and progesterone were shown to have varying effects on delayed rectified potassium channel currents, but testosterone always increases the potassium channel currents, resulting in a shorter corrected QT.
To understand the effect of sex hormones on cardiac electrophysiology, studies have been done on postmenopausal women on hormone replacement therapy. These studies have shown that estrogen therapy lengthens the QT interval, while estrogen/progesterone combination therapy overcomes this change. One specific study by Haseroth and colleagues (2000) studied postmenopausal women on estrogen replacement therapy (ERT) compared to progesterone-estrogen replacement therapy (PERT) and measured QT intervals. They found that PERT significant reduced QT interval dispersion compared to control group and that ERT significantly prolonged QT intervals (QTc mean (ms): 423±28 vs. 398±31; P< 0.05) without affecting dispersion. This study showed that sex hormones modulate ventricular repolarization in vivo and that while estrogen increases QT intervals, simultaneous progestin administration may overcome and negate these effects on QT interval length.
Taking what was learned from postmenopausal studies and applying it to adolescents, Kean and colleagues (2021) looked at progestin-only hormone treatment and its effect on QT interval. In post-menarchal females less than 18 years of age, this research group studied QTc in individuals taking exogenous progestin and compared it to those not on therapy and found that the mean QTc was 403 +/-19 milliseconds (ms) vs. 397 +/-15 ms in those treated (p=0.22). This study showed that individuals on progestin therapy had a shorter QTc by the same magnitude difference (six ms) as the hormonal naïve group mirroring studies done in the adult literature. Overall, there were no adverse effects of progestin associated with QTc prolongation and a trend suggesting a decreased QTc in a population of post menarcheal-adolescent females.
Overall, we know that progestin is the dominant sex hormone responsible for shortening QTc in females. However, can this effect be used as a therapy in those with QTc prolongation caused by drugs? Previous studies have also shown that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening. Tisdale and colleagues (2016) performed a randomized, double blind, placebo-controlled crossover study in which they took 19 healthy females between 21-40 years and randomized them to receive progesterone 400mg or placebo once daily for 7 days. On the 7th day, they infused ibutilide 0.003 mg/kg (known to prolong QT interval) into all participants and recorded QT intervals. They found that those receiving progesterone had lower QTc length before ibutilide and had a lower increased QTc after administration of ibutilide compared to the placebo. This study suggests that oral progesterone can mitigate QTc prolongation effect of drugs.
Can progestin then be used in genetic long QT syndrome to help shorten QT interval? The above studies would suggest perhaps yes, however a literature review revealed that it could be dangerous. Long QT syndrome is a genetic disorder with prolonged ventricular repolarization commonly associated with syncope, cardiac arrest, and sudden cardiac death. In LQT genotype 1 (LQT1) and LQT genotype 2 (LQT2), the delayed rectifier potassium-channels are affected. Previous studies have shown that women with LQTS experience more events after adolescence, post-partum, and perimenopause and that in men, events decrease after adolescence. This effect is most pronounced in LQT2. What effect do oral contraceptive pills (OCPs) have on LQTS given influence of estrogen and progestin and are they safe? A recent study suggests, perhaps not.
Goldenberg and colleagues (2022) reported on 1659 women from 2010-2021 22% who were taking an OCP to look at the effects of various formulations of OCPs (progestin only, estrogen only, progestin-estrogen combination) on risk of cardiac events (CEs) originating from arrhythmias. They found that there was actually a 2.8 fold (p = 0.01) increased risk of CE in women on progestin only who did not receive beta blocker therapy while beta blockers were highly protective during progestin only OC treatment. They did not see this deleterious effect with other formulations of OCPs. This effect was most pronounced in women with LQT2. Why might this be? Theories suggest that perhaps it depends on the generation of progesterone. Studies have shown that women taking 1st/2nd generation progestins had shorter QTc intervals than women not using progesterone but women taking 4th generation progestins had a longer QTc than nonusers. Another study showed patients treated with 4th generation progestin and sotalol had significant QTc prolongation but that levonorgestrel (second generation) combined with sotalol did not cause QTc prolongation. This may be due to the varying estrogenic, progestational, and androgenic components of differing generations of progestins. Other theories suggest that maybe higher concentrations of both hormones are actually needed to observe any effect either protective (progesterone) or harmful (estrogen).
It is clear that more studies are needed to examine the effects of exogenous hormones on electrophysiology, particularly in those with genetic syndromes such as LQTS. What clinical uses does oral progestin have regarding its QT effects and is this effect of progestin only OCPs in LQTS reliable? Further studies are needed to explore the potentially clinical significance of progestin as an attenuator of QT interval prolongation as well as its risks in those with underlying genetic disorders.
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