Drug-induced QT prolongation in women during the menstrual cycle.
BACKGROUND
Women have a higher incidence of torsades de pointes than men, but it is not known if the risk of drug-induced torsades de pointes varies during the menstrual cycle.


OBJECTIVE
To determine if the degree of QT prolongation in response to ibutilide varies with the menstrual cycle phase and to compare QT prolongation between women and men.


METHODS
Cohort study of men and women who received the same intervention conducted between November 1998 and November 2000 at a general clinical research center of a university hospital.


METHODS
A volunteer sample of 58 healthy adults (38 men and 20 women) aged 21 to 40 years.


METHODS
A low dose of ibutilide (0.003 mg/kg), infused intravenously for 10 minutes. Subjects were monitored for 120 minutes. Women received the intervention on 3 separate occasions to correspond with menstrual cycle phases, which were verified by using hormonal assays.


METHODS
QT interval, recorded from electrocardiogram at timed intervals during and after ibutilide infusion and standardized for variations in heart rate (QTc).


RESULTS
Maximum (mean [SD]) millisecond increase in QTc after ibutilide infusion was greater for women during menses (63 [13]) and the ovulatory phase (59 [17]) compared with women during the luteal phase (53 [14]) and compared with men (46 [16]; P =.002 vs menses and P =.007 vs ovulation). Progesterone (r = -0.40) and progesterone-to-estradiol ratio (r = -0.41), but not estradiol (r = 0.14) or testosterone (r = 0.09), were inversely correlated with ibutilide-induced QT prolongation.


CONCLUSIONS
Menstrual cycle and sex differences exist in QTc responses to ibutilide, with the greatest increase in QTc corresponding to the first half of the menstrual cycle.
Rodriguez
I
I
Georgetown University Medical Center, 3900 Reservoir Rd NW, Med-Dent Bldg, Room SE 402, Washington, DC 20007, USA.
Kilborn
M J
MJ
Liu
X K
XK
Pezzullo
J C
JC
Woosley
R L
RL
D000328:Adult; D000704:Analysis of Variance; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D004562:Electrocardiography; D004958:Estradiol / Q000097:blood; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008597:Menstrual Cycle / Q000502:physiology*; D011374:Progesterone / Q000097:blood; D012307:Risk Factors; D012737:Sex Factors; D013449:Sulfonamides / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D013739:Testosterone / Q000097:blood; D016171:Torsades de Pointes / Q000139:chemically induced*
D000889:Anti-Arrhythmia Agents; D013449:Sulfonamides; C067192:ibutilide; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol