Table.1.

Details of the seven cases of TdP identified with hypogonadism

Patient	Past medical history	Clinical presentation	Characterization of hypogonadism†*	Other liable drugs or conditions for TdP†	Outcome
#1, 72 yrs	-Hypertension, normal EF, ischemic cardiomyopathy on betablockers, Langerhans-cell histiocytosis infiltrating multiple organs with BRAF-mutation (ECD) since 2yrs treated by interferon-α -QTc~440ms before ECD; progressive prolongation after ECD: QTc~550ms concomitant to hypogonadism onset	-Respiratory distress and recurrent episodes of TdP, requiring six cardioversions for post-TdP ventricular fibrillation. -QTc>550ms, while on chronic beta-blocker	-No sexual activity with no erection for the past 6–8 months -Clinical examination: bilateral hypotrophic testes, gynecomastia. -Mixed central and peripheral hypogonadism, Bio-T: 0.5ng/ml, FSH: 9.5IU/l, LH:11.6IU/l	-Plasma electrolytes and troponins normal. -Lung infection treated by spiramycin (but, after first episode of syncope)	-ICD implanted -Testosterone started for sustained hypogonadism related to his histiocytosis -QTc normalization within 4 days and no TdP recurrence at 1.5yrs despite vemurafenib introduction (ECD)
#2, 78 yrs	Paroxysmal atrial fibrillation on sotalol and digoxin, normal EF, progressive QTc prolongation over 4 yrs : QTc~460–480ms	-Syncopal TdP episodes 2 days after mitral valve replacement for endocarditis -QTc>600ms, paroxysmal atrio-ventricular blocks	-Progressive apparition of sexual symptoms over the past 5 yrs, probably due to late-onset hypogonadism -Mixed central and peripheral hypogonadism: Bio-T <0.1ng/ml, FSH: 16.6IU/l, LH:10.6IU/l	-Normal electrolytes and no acute ischemia -Bradycardia, paroxysmal atrio-ventricular blocks -Sotalol withdrawn before surgery. Time lag between withdrawal and TdP >5 days	-Temporary pacing -Persistence of QTc~500ms, 2 months after surgery -Testosterone administration at 3 months with normalization of sexual symptoms and QTc with no TdP recurrence at 1 yr
#3, 75 yrs	Pacemaker for paroxysmal bradycardia-tachycardia syndrome on amiodarone and bisoprolol (QTc~530ms), ischemic cardiomyopathy, EF: 35–45%, moderate renal failure	-Cardiac arrest on TdP 12h after elective pacemaker replacement -QTc: 660ms	-Chronic clinical signs of hypogonadism, probably due to late-onset hypogonadism -Peripheral hypogonadism: Bio-T <0.1ng/ml, FSH:44.9IU/l, LH:51.3IU/l	-Normal electrolytes and no acute ischemia -Hydroxyzine before surgery, chronic amiodarone	-Persistence of QTc~550ms 1 week after amiodarone and hydroxyzine withdrawal -Testosterone administration 1 week post TdP with QTc shortening (~480ms) and no TdP recurrence at 3 months
#4, 90 yrs	Hypertension treated with diuretics, normal EF, borderline QTc (~460ms), cured prostate cancer, temporal arteritis on corticosteroids	-Syncopal TdP episodes requiring cardioversions in a context of paroxysmal atrial fibrillation and sepsis -QTc>600ms	-Mild chronic clinical signs of hypogonadism -Mixed central and peripheral hypogonadism; Bio-T: 0.2ng/ml, FSH: 17.5IU/l, LH:20IU/l	-Severe hypokalemia (2mmol/l) -Sepsis treated by ciprofloxacin and fluconazole	-Correction of hypokalemia, withdrawal of liable drugs -Spontaneous incomplete reversion of Bio-T: 0.7ng/ml, and shortening of QTc (486ms) within 10 days -Testosterone not given (history of prostate cancer)
#5, 63 yrs	Hypertension, prostate adenoma, familial history of sudden death, normal QTc, normal EF, paroxysmal atrial fibrillation	-Multiple self-terminating TdP episodes in context of septic and hemorrhagic shocks -QTc: 508 ms	-No pre-existing signs of hypogonadism before shock -Central hypogonadism triggered by severe acute conditions; Bio-T <0.1ng/ml, FSH: 6.9IU/l, LH:10.7IU/l	-Shocks, extra-corporeal membrane oxygenation -Ventricular arrhythmias and ischemia on inotropes requiring amiodarone	-Spontaneous normalization of T-levels (Bio-T: 0.9ng/ml), and QTc (440ms) one month after recovery from shock
#6, 63 yrs	Hypertension, paroxysmal atrial fibrillation, systemic aneurysmal vasculopathy leading to multiple strokes complicated by epilepsy and hemiplegia, Normal EF, Normal QTc	-Cardiac arrest due to TdP leading to ventricular fibrillation (>15 cardioversions) -QTc~560ms	-No pre-existing signs of hypogonadism before TdP -Central hypogonadism triggered by acute severe conditions; Bio-T: 0.3ng/ml, FSH: 6.4IU/l, LH:4.4IU/l	-Normal electrolytes and no acute ischemia	Septic death 6 days after admission for cardiac arrest
#7, 72 yrs	Syncopal sinus node dysfunction with normal QTc requiring pacemaker, hypertension, normal EF, normal QTc	-TdP (QTc: 470ms) while hospitalized for transient cerebral ischemia -Recurrence of acquired prolonged QTc: 480ms, in context of endocarditis	-No pre-existing signs of hypogonadism before TdP -Central hypogonadism triggered by acute severe conditions; Bio-T< 0.1ng/ml, FSH: 0.5IU/l, LH:1.4IU/l (for endocarditis event)	-Normal electrolytes and no acute ischemia	-Spontaneous normalization of T-levels (Bio-T: 1.5ng/ml), and QTc (430ms) within weeks of acute events resolution -ICD upgrading while changing pacemaker

Abbreviations: Bio-T: bioavailable testosterone; ECD: Erdheim-Chester disease; EF: ejection fraction (left ventricle); FSH: Follicle stimulating hormone; ICD: implantable cardioverter defibrillator; LH: luteinizing hormone; ms: milliseconds; TdP: Torsade de Pointes, yrs: years

^*Hypogonadic men with high FSH and LH were classified as having peripheral hypogonadism, whereas those with inappropriately normal or low FSH and LH were considered to have central hypogonadism. Normal values for adult men in our laboratory: FSH: 1.5–12.4 IU/l, LH: 1.7–8.6 IU/l, Bio-T: 1–3.2 ng/ml. A progressive decrease of Bio-T normal values are expected with increasing age (up to 40% at 90y).

^†According to CredibleMeds website: https://crediblemeds.org/