Male Reproduction and Aging.

Recent publications of well-conducted population studies have informed us that the syndromic prevalence of age-related low testosterone, also known as late-onset hypogonadism, is quite low. Several well-conducted trials in middle-aged and older men with age-related decline in testosterone levels have revealed that efficacy of testosterone therapy is modest with improvement in sexual function, mood, volumetric bone density, and anemia. Although select older men might benefit from testosterone therapy, its effect on prostate cancer risk and major adverse cardiovascular events remains unclear. The results of the ongoing TRAVERSE trial will likely provide important insights into these risks.

The medicalization of testosterone: reinventing the elixir of life.

The pursuit of longevity, which during the Renaissance era was limited to longing for miraculous ways of rejuvenation, such as bathing in the fountain of youth, took a scientific turn in 1889 with the publication of Brown-Sequard's self-experiments with an extract of animal testes, which apparently improved his vitality, physical strength and cognition. This extract, marketed then as the "Elixir of Life", was sold for decades throughout Europe and North America. However, recent replication of Brown-Sequard's experiments demonstrated that such an extract only contains homeopathic concentrations of testosterone that are insufficient to exert any biological effect. Thus, the birth of Andrology began with a placebo effect. Over the past few decades, the quest for compounds that might lead to rejuvenation has regained traction, with testosterone being at the forefront. Though clinical practice guidelines advocate testosterone therapy in men with organic hypogonadism-the only indication approved by the Food and Drug Administration-testosterone continues to be marketed as a wonder drug with rejuvenating effects on sexual function, vitality, and a host of other unproven benefits. Additionally, the epidemic of obesity and diabetes, conditions associated with low testosterone, has further brought testosterone into the limelight. Although the number of testosterone prescriptions written have increased several-fold in the past two decades, carefully conducted randomized trials suggest modest benefits of testosterone therapy. At the same time, safety concerns, particularly in older men, remain valid.

Testosterone Therapy With Subcutaneous Injections: A Safe, Practical, and Reasonable Option.

CONTEXT: Injections with intramuscular (IM) testosterone esters have been available for almost 8 decades and not only result in predictable serum testosterone levels but are also the most inexpensive modality. However, they are difficult to self-administer and associated with some discomfort. Recently, subcutaneous (SC) administration of testosterone esters has gained popularity, as self-administration is easier with this route. Available data, though limited, support the feasibility of this route. Here we review the pharmacokinetics and safety of SC testosterone therapy with both long- and ultralong-acting testosterone esters. In addition, we provide guidance for clinicians on how to counsel and manage their patients who opt for the SC route. EVIDENCE ACQUISITION: Systematic review of available literature on SC testosterone administration including clinical trials, case series, and case reports. We also review the pharmacology of testosterone absorption after SC administration. EVIDENCE SYNTHESIS: Available evidence, though limited, suggests that SC testosterone therapy in doses similar to those given via IM route results in comparable pharmacokinetics and mean serum testosterone levels. With appropriate training, patients should be able to safely self-administer testosterone esters SC with relative ease and less discomfort compared with the IM route. CONCLUSION: Although studies directly comparing the safety of SC vs IM administration of testosterone esters are desirable, clinicians should consider discussing the SC route with their patients because it is easier to self-administer and has the potential to improve patient adherence.

Age Trends in Growth and Differentiation Factor-11 and Myostatin Levels in Healthy Men, and Differential Response to Testosterone, Measured Using Liquid Chromatography-Tandem Mass Spectrometry.

BACKGROUND: Growth and differentiation factor (GDF)-11 controls embryonic development and has been proposed as an antiaging factor. GDF-8 (myostatin) inhibits skeletal muscle growth. Difficulties in accurately measuring circulating GDF-11 and GDF-8 have generated controversy. METHODS: We developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous measurement of circulating GDF-8 and GDF-11 that employs denaturation, reduction, and alkylation; cation-exchange solid-phase extraction; tryptic digestion; followed by separation and quantification using 2 signature peptides for multiple reaction monitoring and C-terminal [13C615N4]-Arg peptides as internal standards. We evaluated age trends in serum GDF-11 and GDF-8 concentrations in community-dwelling healthy men, 19 years or older, and determined the effects of graded testosterone doses on GDF-8 and GDF-11 concentrations in healthy men in a randomized trial. RESULTS: The assay demonstrated linearity over a wide range, lower limit of quantitation 0.5 ng/mL for both proteins, and excellent precision, accuracy, and specificity (no detectable cross-reactivity of GDF-8 in GDF-11 assay or of GDF-11 in GDF-8 assay). Mean ± SD (median ± 1QR) GDF-8 and GDF-11 levels in healthy community-dwelling men, 19 years and older, were 7.2 ±â€…1.9 (6.8 ±â€…1.4) ng/mL. Neither GDF-8 nor GDF-11 levels were related to age or body composition. Testosterone treatment significantly increased serum GDF-8 but not GDF-11 levels. CONCLUSIONS: The LC-MS/MS method for the simultaneous measurement of circulating total GDF-8 and GDF-11 demonstrates the characteristics of a valid assay. Testosterone treatment increased GDF-8 levels, but not GDF-11. Increase in GDF-8 levels by testosterone treatment, which increased muscle mass, suggests that GDF-8 acts as a chalone to restrain muscle growth.

Effect of Protein Intake on Visceral Abdominal Fat and Metabolic Biomarkers in Older Men With Functional Limitations: Results From a Randomized Clinical Trial.

BACKGROUND: It remains controversial whether high protein diets improve cardiometabolic profile. We investigated whether increasing protein intake to 1.3 g/kg/day in functionally limited older adults with usual protein intake ≤RDA (0.8 g/kg/day) improves visceral fat accumulation and serum cardiovascular risk markers more than the recommended daily allowance (RDA). METHODS: The Optimizing Protein Intake in Older Men Trial was a placebo-controlled, randomized trial in which 92 functionally limited men, ≥65 years, with usual protein intake ≤RDA were randomized for 6 months to: 0.8 g/kg/day protein plus placebo; 1.3 g/kg/day protein plus placebo; 0.8 g/kg/day protein plus testosterone enanthate 100 mg weekly; or 1.3 g/kg/day protein plus testosterone enanthate 100 mg weekly. In this substudy, metabolic and inflammatory serum markers were measured in 77 men, and visceral adipose tissue (VAT) was assessed using dual-energy x-ray absorptiometry in 56 men. RESULTS: Treatment groups were similar in their baseline characteristics. Randomization to 1.3 g/kg/day protein group was associated with greater reduction in VAT compared to 0.8 g/kg/day group (between-group difference: -17.3 cm2, 95% confidence interval [CI]: -29.7 to -4.8 cm2, p = .008), regardless of whether they received testosterone or placebo. Changes in fasting glucose, fasting insulin, HOMA-IR, leptin, adiponectin, IL-6, and hs-CRP did not differ between the 0.8 versus 1.3 g/kg/day protein groups regardless of testosterone use. CONCLUSIONS: Protein intake >RDA decreased VAT in functionally limited older men but did not improve cardiovascular disease risk markers. CLINICAL TRIALS REGISTRATION NUMBER: NCT01275365.

Differential effects of testosterone on circulating neutrophils, monocytes, and platelets in men: Findings from two trials.

BACKGROUND: Testosterone treatment increases erythrocytes in men, but its effects on leukocyte and platelet counts are unknown and could affect its safety. OBJECTIVE: To determine whether testosterone affects circulating leukocytes and platelets in men. METHODS: Secondary analyses of two randomized testosterone trials were performed: the 5α-reductase (5aR) and OPTIMEN trials. In 5aR trial, 102 healthy men, 21-50 years (mean age 38), received a long-acting GnRH agonist, and 50, 125, 300, or 600 mg/week testosterone enanthate (TE) plus placebo or 2.5 mg/ day dutasteride for 20 weeks. In OPTIMEN, 78 functionally limited men, ≥65 years (mean age 72) with protein intake ≤ 0.83 g kg-1  day-1 , were randomized to controlled diets with 0.8 g kg-1  day-1 protein or 1.3 g kg-1  day-1 protein plus placebo or TE (100 mg/week) for 6 months. Changes from baseline in total and differential leukocyte count, and platelet count were evaluated. RESULTS: In 5aR, testosterone administration was associated with increases in total leukocyte (estimated change from baseline 40, 490, 1230, and 1280 cells/µL, P < .001), neutrophil (65.1, 436.1, 1177.2, and 1192.2 cells/µL, P < .001), monocyte (-20.2, 24.5, 90.6, and 143.9 cells/µL, P < .001), platelet (-7.3, 8.4, 8.7, and 8.9 × 103 cells/µL, P = .033), and erythrocyte counts. Testosterone did not affect absolute lymphocyte count. Similar increase in total leukocyte count was observed with testosterone treatment in OPTIMEN (change 0.77 × 103 cells/µL, P vs placebo = 0.004). CONCLUSIONS: Testosterone administration in men differentially increases neutrophil and monocyte counts. These findings, together with its erythropoietic effects, suggest that testosterone promotes the differentiation of hematopoietic progenitors into the myeloid lineage. These findings have potential mechanistic, therapeutic, and safety implications.

The Stair Climb Power Test as an Efficacy Outcome in Randomized Trials of Function Promoting Therapies in Older Men.

BACKGROUND: Standardization of performance-based physical function measures that are reliable and responsive to intervention is necessary for efficacy trials of function promoting anabolic therapies (FPTs). Herein, we describe a standardized method of measuring stair climbing power (SCP) and evaluate its ability to assess improvements in physical function in response to an FPT (testosterone) compared to gait speed. METHODS: We used a 12-step SCP test with and without carrying a load (loaded, LSCP or unloaded, USCP) in two testosterone trials in older men. SCP was determined from mass, total step-rise, and time of ascent measured with an electronic timing system. Associations between SCP and leg press performance (strength and power), testosterone levels, and gait speed were assessed. Test-retest reliability was evaluated using interclass correlation and Bland-Altman analyses. RESULTS: Baseline SCP was negatively associated with age and positively with leg strength and power and gait speed. Both tests of SCP were safe and showed excellent reliability (intra-class correlation 0.91-0.97 in both cohorts). Changes in testosterone concentrations were associated with changes in USCP and LSCP, but not gait speed in mobility-limited men. Changes in leg press performance were associated with SCP in both trials. CONCLUSIONS: Both USCP and LSCP are safe and have high test-retest reliability. Compared to gait speed, SCP is associated more robustly with leg press performance and is sensitive to testosterone therapy. The LSCP might be a more responsive outcome than gait speed to evaluate the efficacy of FPT in randomized trials.

Testosterone replacement therapy and cardiovascular risk.

Testosterone is the main male sex hormone and is essential for the maintenance of male secondary sexual characteristics and fertility. Androgen deficiency in young men owing to organic disease of the hypothalamus, pituitary gland or testes has been treated with testosterone replacement for decades without reports of increased cardiovascular events. In the past decade, the number of testosterone prescriptions issued for middle-aged or older men with either age-related or obesity-related decline in serum testosterone levels has increased exponentially even though these conditions are not approved indications for testosterone therapy. Some retrospective studies and randomized trials have suggested that testosterone replacement therapy increases the risk of cardiovascular disease, which has led the FDA to release a warning statement about the potential cardiovascular risks of testosterone replacement therapy. However, no trials of testosterone replacement therapy published to date were designed or adequately powered to assess cardiovascular events; therefore, the cardiovascular safety of this therapy remains unclear. In this Review, we provide an overview of epidemiological data on the association between serum levels of endogenous testosterone and cardiovascular disease, prescription database studies on the risk of cardiovascular disease in men receiving testosterone therapy, randomized trials and meta-analyses evaluating testosterone replacement therapy and its association with cardiovascular events and mechanistic studies on the effects of testosterone on the cardiovascular system. Our aim is to help clinicians to make informed decisions when considering testosterone replacement therapy in their patients.

Oral glucose load and mixed meal feeding lowers testosterone levels in healthy eugonadal men.

PURPOSE: Precise evaluation of serum testosterone levels is important in making an accurate diagnosis of androgen deficiency. Recent practice guidelines on male androgen deficiency recommend that testosterone be measured in the morning while fasting. Although there is ample evidence regarding morning measurement of testosterone, studies that evaluated the effect of glucose load or meals were limited by inclusion of hypogonadal or diabetic men, and measurement of testosterone was not performed using mass spectrometry. METHODS: Sixty men (23-97 years) without pre-diabetes or diabetes who had normal total testosterone (TT) levels underwent either an oral glucose tolerance test (OGTT) or a mixed meal tolerance test (MMTT) after an overnight fast. Serum samples were collected before and at regular intervals for 2 h (OGTT cohort) or 3 h (MMTT cohort). TT was measured by LC-MS/MS. LH and prolactin were also measured. RESULTS: TT decreased after a glucose load (mean drop at nadir = 100 ng/dL) and after a mixed meal (drop at nadir = 123 ng/dL). Approximately 11% of men undergoing OGTT and 56% undergoing MMTT experienced a transient decrease in TT below 300 ng/dL, the lower normal limit. Testosterone started declining 20 min into the tests, with average maximum decline at 60 min. Most men still had TT lower than baseline at 120 min. This effect was independent of changes in LH or prolactin. CONCLUSION: A glucose load or a mixed meal transiently, but significantly, lowers TT levels in healthy, non-diabetic eugonadal men. These findings support the recommendations that measurement of serum testosterone to diagnose androgen deficiency should be performed while fasting.

Mechanisms responsible for reduced erythropoiesis during androgen deprivation therapy in men with prostate cancer.

Androgen deprivation therapy (ADT) is a mainstay of treatment for prostate cancer (PCa). As androgens stimulate erythropoiesis, ADT is associated with a reduction in hematocrit, which in turn contributes to fatigue and related morbidity. However, the mechanisms involved in ADT-induced reduction in erythropoiesis remain unclear. We conducted a 6-mo prospective cohort study and enrolled men with PCa about to undergo ADT (ADT-Group) and a control group of men who had previously undergone prostatectomy for localized PCa and were in remission (Non-ADT Group). All participants had normal testosterone levels at baseline. Fasting blood samples were collected at baseline, 12 wk, and 24 wk after initiation of ADT; samples were obtained at the same intervals from enrollment in the Non-ADT group. Blood count, iron studies, erythropoietin, erythroferrone, and hepcidin levels were measured. Seventy participants formed the analytical sample (31 ADT, 39 Non-ADT). ADT was associated with a significant reduction in erythrocyte count (estimated mean difference = -0.2×106 cells/µl, 95%CI = -0.3 to -0.1×106 cells/µl, P < 0.001), hematocrit (-1.9%, 95%CI = -2.7 to -1.1%, P < 0.001), and hemoglobin (-0.6 g/dl, 95%CI = -0.8 to -0.3 g/dl, P < 0.001). Serum hepcidin concentration increased in the ADT-group (18 ng/ml, P < 0.001); however, iron concentrations did not change (-1.1 µg/dl, P = 0.837). Ferritin levels increased in men on ADT (60 ng/ml, P < 0.001). Iron binding capacity, transferrin saturation, erythroferrone, and erythropoietin did not change. Nine men undergoing ADT developed new-onset anemia. In conclusion, reduced proliferation of marrow erythroid progenitors leads to ADT-induced reduction in erythropoiesis. Future studies should evaluate the role of selective androgen receptor modulators in the treatment of ADT-induced anemia.

Effects of an ActRIIB.Fc Ligand Trap on Cardiac Function in Simian Immunodeficiency Virus-Infected Male Rhesus Macaques.

An important safety consideration in the use of antagonists of myostatin and activins is whether these drugs induce myocardial hypertrophy and impair cardiac function. The current study evaluated the effects of a soluble ActRIIB receptor Fc fusion protein (ActRIIB.Fc), a ligand trap for TGF-ß/activin family members including myostatin, on myocardial mass and function in simian immunodeficiency virus (SIV)-infected juvenile rhesus macaques (Macaca mulatta). Fourteen pair-housed, juvenile male rhesus macaques were inoculated with SIVmac239; 4 weeks postinoculation, they were treated with weekly injections of 10 mg/kg ActRIIB.Fc or saline for 12 weeks. Myocardial mass and function were evaluated using two-dimensional echocardiography at baseline and after 12 weeks. The administration of ActRIIB.Fc was associated with a significantly greater increase in thickness of left ventricular posterior wall and interventricular septum both in diastole and systole. Cardiac output and cardiac index increased with time, more in animals treated with ActRIIB.Fc than in those treated with saline, but the difference was not statistically significant. The changes in ejection fraction, fractional shortening, and stroke volume did not differ significantly between groups. The changes in end-diastolic and end-systolic volumes did not differ between groups. In addition to a large reduction in IGF1 mRNA expression in the ActRIIB.Fc-treated animals, complex changes were detected in the myocardial expression of proteins related to calcium transport and storage. In conclusion, ActRIIB.Fc administration for 12 weeks was associated with increased myocardial mass but did not adversely affect myocardial function in juvenile SIV-infected rhesus macaques. Further studies are necessary to establish long-term cardiac safety.

Metabolic Changes in Androgen-Deprived Nondiabetic Men With Prostate Cancer Are Not Mediated by Cytokines or aP2.

Context: Androgen deprivation therapy (ADT) remains the cornerstone of management of prostate cancer (PCa). Previous studies have shown that men undergoing ADT develop insulin resistance and diabetes, but the mechanisms behind ADT-induced metabolic abnormalities remain unclear. Objective: To evaluate the role of inflammatory cytokines and adipocyte protein-2 (aP2) in ADT-induced metabolic dysfunction. Participants and Interventions: This 6-month prospective cohort study enrolled nondiabetic men with PCa about to undergo ADT (ADT group) and a control group of nondiabetic men who had previously undergone prostatectomy for localized PCa and were in remission (non-ADT group); all participants had normal testosterone at study entry. Fasting blood samples were collected at baseline and at 6, 12, and 24 weeks after initiation of ADT and at the same intervals in the non-ADT group. Glucose, insulin, lipids, inflammatory cytokines, and C-reactive protein were measured. We also measured serum aP2, an adipocyte-secreted protein that promotes hepatic glucose production. Homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. Results: Seventy-three participants formed the analytical sample (33 ADT, 40 non-ADT). HOMA-IR increased in the ADT group (estimated change = 0.25; P = 0.05), but was unchanged in the non-ADT group (0.11; P = 0.342). Serum concentrations of inflammatory cytokines or aP2 did not change significantly. There was a treatment-associated increase in total (16 mg/dL; P < 0.001), high-density lipoprotein (8 mg/dL; P < 0.001), and low-density lipoprotein (7 mg/dL; P = 0.02) cholesterol. Conclusion: ADT-induced metabolic abnormalities were not associated with changes in circulating inflammatory cytokines or aP2 levels.

Androgen Deprivation Therapy Is Associated With Prolongation of QTc Interval in Men With Prostate Cancer.

CONTEXT: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with increased cardiovascular mortality and sudden cardiac death, with some events occurring early after initiation of ADT. Testosterone levels are inversely associated with corrected QT (QTc) interval duration; therefore, prolongation of QTc duration could be responsible for some of these events during ADT. OBJECTIVE: To evaluate changes in QTc duration during ADT. DESIGN AND INTERVENTIONS: A 6-month prospective cohort study that enrolled men with PCa about to undergo ADT (ADT group) and a control group of men who previously underwent prostatectomy for PCa and never received ADT (non-ADT group). PATIENTS: At study entry, all participants were eugonadal and had no history of cardiac arrhythmias or complete bundle branch block. OUTCOMES: Difference in change in QTc duration from baseline on a 12-lead electrocardiogram at 6, 12, and 24 weeks after initiation of ADT compared with electrocardiograms performed at the same intervals in the non-ADT group. PR, QRS, and QT interval durations were also evaluated. RESULTS: Seventy-one participants formed the analytical sample (33 ADT and 38 non-ADT). ADT was associated with prolongation of the QTc by 7.4 ms compared with the non-ADT group [95% confidence interval (CI) 0.08 to 14.7 ms; P = 0.048]. ADT was also associated with shortening of the QRS interval by 2.4 ms (95% CI -4.64 to -0.23; P = 0.031). Electrolytes did not change. CONCLUSIONS: Men undergoing ADT for PCa experienced prolongation of the QTc. These findings might explain the increased risk of sudden cardiac death seen in these patients.

Effects of Androgen Deprivation Therapy on Pain Perception, Quality of Life, and Depression in Men With Prostate Cancer.

CONTEXT: Previous animal and human research suggests that testosterone has antinociceptive properties. Castration in male rodents increases pain perception which is reversed by testosterone replacement. Pain perception also improves in hypogonadal men with testosterone therapy. However, it remains unclear whether androgen deprivation therapy (ADT) in men with prostate cancer (PCa) is associated with an increase in pain perception. OBJECTIVES: To evaluate the effects of ADT on pain perception, depression and quality of life (QOL) in men with PCa. METHODS: Thirty-seven men with PCa about to undergo ADT with leuprolide acetate (ADT group) were followed prospectively for six months to evaluate changes in clinical and experimental pain. Forty men who had previously undergone prostatectomy for localized PCa and were in remission served as controls (non-ADT group). All participants were eugonadal at study entry. Primary outcomes were changes in clinical pain (assessed with Brief Pain Inventory questionnaire) and experimental pain (assessed with quantitative sensory testing). Secondary outcomes included evaluation of depression, anxiety levels, and quality of life. RESULTS: Serum testosterone levels significantly decreased in the ADT group but remained unchanged in the non-ADT group. There were no significant changes in pain thresholds, ratings, or other responses to quantitative sensory tests over the 6-month course of the study. Clinical pain did not differ between the two groups, and no changes from baseline were observed in either group. Men undergoing ADT did experience worsening of depression (0.93; 95% CI = 0.04-1.82; P = 0.042) and QOL related to physical role limitation (-18.28; 95% CI = -30.18 to -6.37; P = 0.003). CONCLUSION: ADT in men with PCa is associated with worsening of depression scores and QOL but is not associated with changes in clinical pain or pain sensitivity.

Trials of testosterone replacement reporting cardiovascular adverse events.

The numbers of testosterone prescriptions written have increased several-fold worldwide, but the incidence of pathological hypogonadism due to hypothalamic, pituitary, and testicular disease has remained unchanged. Most of these prescriptions are being dispensed to middle-aged and older men who have experienced age-related decline in serum testosterone levels; a subset of the population in which benefits of testosterone replacement is at best, modest. Recently, some randomized controlled trials have reported increased cardiovascular events in men (mainly older men and those with prevalent cardiovascular disease) with testosterone use, and a few recent meta-analyses have confirmed these findings. In this review, we discuss trials of testosterone therapy that have reported higher cardiovascular events, relevant trials that have not reported increased cardiovascular events and large trials that have focused on cardiovascular risk (mainly atherosclerosis progression) as their main outcome. We also review findings from meta-analyses that have evaluated cardiovascular events in various testosterone trials. Finally, we discuss some potential mechanisms by which testosterone use might result in an increased cardiovascular risk. As none of the trials conducted to date were adequately powered to evaluate cardiovascular events, no firm conclusions can be drawn regarding the cardiovascular safety of testosterone therapy at this time. In the interim, we hope that this review will help practitioners make informed decisions regarding the care of their patients.

Effects of Testosterone Replacement on Electrocardiographic Parameters in Men: Findings From Two Randomized Trials.

Context: Endogenous testosterone levels have been negatively associated with QTc interval in small case series; the effects of testosterone therapy on electrocardiographic parameters have not been evaluated in randomized trials. Objective: To evaluate the effects of testosterone replacement on corrected QT interval (QTcF) in two randomized controlled trials. Participants: Men with pre- and postrandomization electrocardiograms (ECGs) from the Testosterone and Pain (TAP) and the Testosterone Effects on Atherosclerosis in Aging Men (TEAAM) Trials. Interventions: Participants were randomized to either placebo or testosterone gel for 14 weeks (TAP) or 36 months (TEAAM). ECGs were performed at baseline and at the end of interventions in both trials; in the TEAAM trial ECGs were also obtained at 12 and 24 months. Outcomes: Difference in change in the QTcF between testosterone and placebo groups was assessed in each trial. Association of changes in testosterone levels with changes in QTcF was analyzed in men assigned to the testosterone group of each trial. Results: Mean total testosterone levels increased in the testosterone group of both trials. In the TAP trial, there was a nonsignificant reduction in mean QTcF in the testosterone group compared with placebo (effect size = -4.72 ms; P = 0.228) and the changes in QTcF were negatively associated to changes in circulating testosterone (P = 0.036). In the TEAAM trial, testosterone attenuated the age-related increase in QTcF seen in the placebo group (effect size= -6.30 ms; P < 0.001). Conclusion: Testosterone replacement attenuated the age-related increase in QTcF duration in men. The clinical implications of these findings require further investigation.