Hypogonadism as a Reversible Cause of Torsades de Pointes in Men
Long QT intervals corrected for rate (QTc) >480 to 500 milliseconds predispose to the polymorphic ventricular tachycardia torsades de pointes (TdP).1 Because QTc is shorter and TdP is less frequent in men than in women and because testosterone shortens ventricular repolarization, we examined the effect of hypogonadism and androgen deprivation therapy (ADT) on QTc and TdP risk.2
We prospectively evaluated testosterone and related plasma levels in each man seen with TdP (n=7) over 19 months at a single university hospital (Hôpital Pitié-Salpétrière, Paris, France, Commission nationale de l’informatique et des libertés No. 1491960v0, patients’ informed consent obtained). We then analyzed the European pharmacovigilance database (up to June 2017, URL: https://clinicaltrials.gov, Unique identifier: NCT03193138) searching for QTc/TdP adverse drug reactions (Medical Dictionary for Regulatory Activities terms: long-QT syndrome [LQT], ECG QT-prolonged, and TdP) associated with ADT, and we performed a cross-sectional analysis of the association between the International Classification of Diseases revisions 9 and 10 codes for LQT/TdP and hypogonadism in 1.1 million men in a US electronic health record cohort (up to November 2017, Vanderbilt University Medical Center, Institutional Review Board approval no. 171796).3
Hypogonadism was diagnosed in 7 of 7 cases of TdP (Table). After correction of low testosterone levels, QTc shortened and there was no TdP recurrence. Three patients had spontaneous reversal of hypogonadism after resolution of a severe critical illness; 3 patients needed testosterone supplementation for chronic hypogonadism; and 1 patient died. LQT genetic screening was negative in 6 of the 6 tested patients.
The European pharmacovigilance database (http://www.adrreports.eu/fr/search.html) analysis identified 43 of 34 221 individual case safety reports of men with drug-induced (di) LQT (diLQT) and 15 of 34 221 with diTdP suspected to be attributable to ADT versus none (0 of 10 847) reported during testosterone replacement therapy. ADT included the following pharmacological classes of drugs: gonadotrophin-releasing hormone receptor agonists (leuprolide, buserelin, goserelin, triptorelin), gonadotrophin-releasing hormone receptor antagonist (degarelix), cytochrome-17 inhibitor (abiraterone), nonsteroidal androgen receptor antagonists (bicalutamide, flutamide, nilutamide, enzalutamide), and 5α-reductase inhibitors (finasteride, dutasteride). Disproportionality analysis showed higher reporting odds ratios (ORs)4 comparing ADT and testosterone for diLQT and diTdP (reporting OR, 3.75–∞, P<0.0001; reporting OR, 1.3–∞, P=0.03; respectively). Degarelix and abiraterone carried the highest reporting rate for diLQT (n=4 of 769 [0.52%] for degarelix; n=7 of 4723 [0.15%] for abiraterone) and diTdP (n=2 of 769 [0.26%] for degarelix; n=5 of 4723 [0.11%] for abiraterone) compared with other ADTs (n=32 of 28 729 [0.11%] for diLQT; n=8 of 28 729 [0.03%] for diTdP; both P<0.05).
In the electronic health record cohort, conditions or drugs leading to hypogonadism were associated with LQT/TdP (86 of 38 041 cases versus 649 of 1 082 891 controls; crude OR, 3.8 [95% confidence interval, 3–4.7]; age-adjusted OR, 4.8 [95% confidence interval, 3.8–6.1]). Men with hypogonadism secondary to endocrine conditions carried the highest association with LQT/TdP compared with ADT users and all other men (30 of 9202 [0.33%] versus 56 of 28 839 [0.19%] versus 649 of 1 082 891 [0.06%], respectively, P<0.0001).
Taken together, these data provide consistent support for an association between hypogonadism in men and LQT/TdP. The association appears to be causal because correction of hypogonadism by testosterone replacement therapy can treat or prevent TdP and ADT can lead to LQT/TdP. These results provide strong justification for a clinical recommendation to investigate the possibility of hypogonadism when TdP occurs in men. Hypogonadism should be added to the list of risk factors for TdP, and an increased awareness should prompt correction of other TdP risk factors in men receiving ADT.
Our findings support the hypothesis that hypogonadism is a correctable and readily identifiable risk factor for TdP in men. There should be a high index of suspicion when symptoms such as erectile dysfunction, testicular hypotrophy, and hot flashes are present, particularly when the prevalence of hypogonadism is expected to be high such as in elderly men. It has been shown that hypothalamic-pituitary-gonadal axis physiology is dramatically altered during critical illnesses and after major surgery or brain injury and can lead to transient functional hypogonadism5; therefore, the distinction between transient hypogonadism in this setting and preexistent hypogonadism may be difficult. For these reasons, we postponed testosterone supplementation in patients 4 through 7 (sepsis, surgery, or stroke; Table), awaiting a spontaneous normalization of pituitary function. Late-onset hypogonadism has recently been defined as a syndrome in middle-aged and elderly men reporting sexual symptoms associated with higher cardiovascular mortality in the presence of low testosterone levels (eg, patients 2 and 3).5 In our case series, TdP did not recur after testosterone supplementation. The basic mechanisms are not completely defined, but preclinical studies show that testosterone increases the repolarizing potassium currents IKr and IKs and decreases the depolarizing L-type calcium current.2
ADT is a cornerstone of the treatment of prostate cancer. Among ADTs, the website crediblemeds.org currently lists only degarelix and leuprolide as possible risks for TdP, so further guideline updates may be needed for newer drugs such as abiraterone.
A limitation of the analyses of the pharmacovigilance database and the electronic health record is that the data come from uncontrolled sources. Nevertheless, the case series and the population analyses provide orthogonal validation for the causal, and treatable, relationship we postulate between male hypogonadism and TdP risk.
Sources of Funding
This study was supported by the Cancer Institut Thématique Multi-Organisme of the French National Alliance for Life and Health Sciences: Plan Cancer 2014 to 2019. The Vanderbilt deidentified electronic medical record has been supported by numerous sources: institutional funding, private agencies, and federal grants. These include the National Institutes of Health–funded Shared Instrumentation Grant S10RR025141 and Clinical and Translational Science Awards grants UL1TR002243, UL1TR000445, and UL1RR024975.
Dr Moslehi has been a consultant to Novartis, Pfizer, Bristol Myers Squibb, and Takeda. The other authors report no conflicts.
Marie Bretagne, Pauline Dureau, Valentin Saqué, Aida Zarhrate-Ghoul, Clément Bourguignon, Monique Leban, Virginie Grouthier, Martino Vaglio.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.118.034282/-/DC1.
Data sharing: The data, analytical methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.
- © 2018 American Heart Association, Inc.
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