Association of Oral Contraceptives With Drug-Induced QT Interval Prolongation in Healthy Nonmenopausal Women

Salem, Joe‐Elie; Dureau, Pauline; Bachelot, Anne; Germain, Marine; Voiriot, P; Lebourgeois, Bruno; Trégouët, David‐Alexandre; Hulot, Jean‐Sébastien; Funck‐Brentano, Christian

doi:10.1001/jamacardio.2018.2251

Cited by 34 publications

(22 citation statements)

References 17 publications

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“…Fridericia‐corrected QT intervals (QT F ) were found to be significantly shorter in women with congenital adrenal hyperplasia, in which progesterone overexpression occurs, than in healthy female controls . QT F intervals were inversely correlated with serum progesterone concentrations and the ratio of serum progesterone:estradiol concentrations …”

Section: Discussionmentioning

confidence: 99%

“…In a study of 11 healthy women between the ages of 18 to 32 years, QT intervals were found to be shorter during the luteal phase of the menstrual cycle, when serum progesterone concentrations are highest, compared to those during the follicular phase . Fridericia‐corrected QT intervals (QT F ) were found to be significantly shorter in women with congenital adrenal hyperplasia, in which progesterone overexpression occurs, than in healthy female controls . QT F intervals were inversely correlated with serum progesterone concentrations and the ratio of serum progesterone:estradiol concentrations …”

Section: Discussionmentioning

confidence: 99%

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Progesterone pretreatment reduces the incidence of drug‐induced torsades de pointes in atrioventricular node‐ablated isolated perfused rabbit hearts

Tisdale

Jaynes

Overholser

et al. 2019

Cardiovasc electrophysiol

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Introduction: Higher progesterone concentrations are protective against druginduced prolongation of ventricular repolarization. We tested the hypothesis that pretreatment with progesterone reduces the incidence of drug-induced torsades de pointes (TdP).Methods and Results: Female New Zealand white rabbits (2.5-3.2 kg) underwent ovariectomy and were randomized to undergo implantation with subcutaneous 21-day sustained release pellets containing progesterone 50 mg (n = 22) or placebo (n = 23). After 20 days, hearts were excised, mounted, and perfused with modified Krebs-Henseleit solution. The atrioventricular (AV) node was destroyed manually. Following a 15-minute equilibration period, hearts were perfused with dofetilide 100 nM for 30 minutes, during which the electrocardiogram was recorded continuously. Incidences of spontaneous TdP, other ventricular arrhythmias and mean QT c intervals were compared. Median serum progesterone concentrations were higher in progesterone vs placebo-treated rabbits (3.8 [range, 2.8-5.1] vs 0.7 [0.4-1.7] ng/mL, P < 0.0001). Median serum estradiol concentrations were similar (58 [22-72] vs 53 [34-62] pg/mL), P = 0.79). The incidence of TdP was lower in hearts from progesterone-treated rabbits (27% vs 61%, P = 0.049). The incidences of bigeminy (36% vs 74%, P = 0.03) and trigeminy (18% vs 57%, P = 0.01) were also lower in hearts from progesterone-treated rabbits. There was no significant difference between groups in incidence of couplets (59% vs 74%, P = 0.54) or monomorphic ventricular tachycardia (14% vs 30%, P = 0.28). Maximum QT c interval and short-term beat-to-beat QT interval variability during dofetilide perfusion were significantly shorter in hearts from progesterone-treated rabbits.Conclusions: Pretreatment with progesterone reduces the incidence of drug-induced TdP, bigeminy, and trigeminy in isolated perfused AV node-ablated rabbit hearts. K E Y W O R D S beat-to-beat variability, dofetilide, isolated perfused heart, progesterone, QT interval, rabbit, torsades de pointes, ventricular arrhythmias J Cardiovasc Electrophysiol. 2019;30:941-949. wileyonlinelibrary.com/journal/jce How to cite this article: Tisdale JE, Jaynes HA, Overholser BR, Sowinski KM, Kovacs RJ. Progesterone pretreatment reduces the incidence of drug-induced torsades de pointes in atrioventricular node-ablated, isolated, perfused rabbit hearts. J Cardiovasc Electrophysiol. 2019;30:941-949.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Progesterone pretreatment reduces the incidence of drug‐induced torsades de pointes in atrioventricular node‐ablated isolated perfused rabbit hearts

Tisdale

Jaynes

Overholser

et al. 2019

Cardiovasc electrophysiol

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“…In a US retrospective study analyzing 410,782 ECGs from 34,676 women on oral contraceptive pills, QTc was found to be shorter in users of first and second generations than non-users ( p < 0.0001) and longer in users of the fourth generation than non-users ( p < 0.0001) [ 75 ]. In a recent cohort of 498 healthy non-menopausal women, drospirenone was associated with increased sotalol-induced QTc prolongation ( + 6–7 ms) as compared to controls or levonorgestrel [ 16 , 76 ]. Salem et al also confirmed this finding using the European pharmacovigilance database with a disproportionality analysis showing higher reporting rates of suspected diLQTS, ventricular arrhythmias and cardiac arrest for drospirenone vs. levonorgestrel [ 76 ].…”

Section: Exogenous Hormonal Therapy and Its Effect On Qtc Variatiomentioning

confidence: 99%

“…LQTS, BrS and ERS favor different forms of malignant ventricular arrhythmias—for example, TdP for LQTS and ventricular tachycardia for BrS and ERS that may lead to ventricular fibrillation (VF) and, if sustained, SCD [ 3 , 8 , 14 , 15 ]. This sex-specific prevalence of LQTS, BrS and ERS is partly explained by the fact that androgens shorten APD and QT duration, while its deprivation has opposite effects [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Sexual Dimorphisms, Anti-Hormonal Therapy and Cardiac Arrhythmias

Grouthier

Moey

Gandjbakhch

et al. 2021

IJMS

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Significant variations from the normal QT interval range of 350 to 450 milliseconds (ms) in men and 360 to 460 ms in women increase the risk for ventricular arrhythmias. This difference in the QT interval between men and women has led to the understanding of the influence of sex hormones on the role of gender-specific channelopathies and development of ventricular arrhythmias. The QT interval, which represents the duration of ventricular repolarization of the heart, can be affected by androgen levels, resulting in a sex-specific predilection for acquired and inherited channelopathies such as acquired long QT syndrome in women and Brugada syndrome and early repolarization syndrome in men. Manipulation of the homeostasis of these sex hormones as either hormonal therapy for certain cancers, recreational therapy or family planning and in transgender treatment has also been shown to affect QT interval duration and increase the risk for ventricular arrhythmias. In this review, we highlight the effects of endogenous and exogenous sex hormones in the physiological and pathological states on QTc variation and predisposition to gender-specific pro-arrhythmias.

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“…This study is consistent with the clinical QT prolongation by estrogens used for ET. Recently, oral contraceptives were reported to increase the risk of TdP based on the administration of d,l -sotalol to healthy female volunteers [ 16 ]. However, to date, no studies have assessed whether oral contraceptive ingredients affect the hERG channel function.…”

Section: Introductionmentioning

confidence: 99%

The Effect of a Synthetic Estrogen, Ethinylestradiol, on the hERG Block by E-4031

Tamura

Sugimoto

et al. 2021

Biomolecules

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Inhibition of K+-conductance through the human ether-a-go-go related gene (hERG) channel leads to QT prolongation and is associated with cardiac arrhythmias. We previously reported that physiological concentrations of some estrogens partially suppress the hERG channel currents by interacting with the S6 residue F656 and increase the sensitivity of hERG blockade by E-4031. Although these studies suggested that clinically used synthetic estrogens with similar structures have the marked potential to alter hERG functions, the hERG interactions with synthetic estrogens have not been assessed. We therefore examined whether ethinylestradiol (EE2), a synthetic estrogen used in oral contraceptives, affects hERG function and blockade by drugs. Supratherapeutic concentrations of EE2 did not alter amplitudes or kinetics of the hERG currents elicited by train pulses at 20 mV (0.1 Hz). On the other hand, EE2 at therapeutic concentrations reduced the degree of hERG current suppression by E-4031. The administration of EE2 followed by E-4031 blockade reversed the current suppression, suggesting that the interaction of EE2 and E-4031 alters hERG at the drug-binding site. The effects of EE2 on hERG blockade raised the possibility that other estrogens, including synthetic estrogens, can alter hERG blockade by drugs that cause QT prolongation and ventricular arrhythmias.

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Association of Oral Contraceptives With Drug-Induced QT Interval Prolongation in Healthy Nonmenopausal Women

Cited by 34 publications

References 17 publications

Progesterone pretreatment reduces the incidence of drug‐induced torsades de pointes in atrioventricular node‐ablated isolated perfused rabbit hearts

Progesterone pretreatment reduces the incidence of drug‐induced torsades de pointes in atrioventricular node‐ablated isolated perfused rabbit hearts

Sexual Dimorphisms, Anti-Hormonal Therapy and Cardiac Arrhythmias

The Effect of a Synthetic Estrogen, Ethinylestradiol, on the hERG Block by E-4031

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