Clinical characterization of men with long QT syndrome and torsades de pointes associated with hypogonadism: A review and pharmacovigilance study.

BACKGROUND: Long QT syndrome (LQTS) can cause the potentially fatal ventricular tachycardia torsades de pointes (TdP). QT interval corrected for heart rate (QTc) is shorter in men than in women, with testosterone contributing to shorten QTc. We recently described male hypogonadism as a reversible risk factor for acquired LQTS and TdP, but the clinical characteristics of such patients have not been characterized. AIMS: To describe the clinical characteristics of men with acquired LQTS or TdP associated with hypogonadism caused by endocrine conditions or androgen deprivation therapy (ADT), and to evaluate the relationship between testosterone concentrations and electrocardiographic changes. METHODS: We searched MEDLINE (to 04 January 2019) and the French pharmacovigilance database (to 09 August 2018) to identify male cases of acquired LQTS and TdP associated with endocrine hypogonadism or ADT; their narratives were gathered from reporting collaborators. RESULTS: We identified seven cases of TdP (one fatal) with endocrine hypogonadism, abnormally long QTc and morphologically abnormal T-wave notches. After reversion of low testosterone concentrations in the surviving patients (N=6), QTc shortened, T-wave morphology normalized and there was no TdP recurrence. Among these cases, none had mutation in the LQTS genes, three men required testosterone and three had reversible hypogonadism after resolution of a concurrent acute severe illness. We found an additional 27 reports of men with LQTS (N=6), TdP (N=9; 2/9 fatal) or sudden death (N=12; 10/12 fatal) suspected to be induced or favoured by ADT (24/27 for prostate cancer). Generally, after ADT withdrawal, QTc shortened and no TdP recurred. CONCLUSION: We propose seeking for hypogonadism caused by endocrine conditions or ADT in men presenting with TdP. Caution is warranted when ADT is used in situations at risk of TdP. Testosterone may be useful to treat or prevent TdP.

Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors.

BACKGROUND: This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy. PATIENTS AND METHODS: Eligible TCS were <55 years of age at diagnosis and treated with first-line platinum-based chemotherapy. Participants underwent physical examinations and completed questionnaires regarding 15 AHOs and health behaviors. Hypogonadism was defined as serum testosterone levels ≤3.0 ng/mL or use of testosterone replacement therapy. We investigated the role of 2 single nucleotide polymorphisms (rs6258 and rs12150660) in the sex hormone-binding globulin (SHBG) locus implicated in increased hypogonadism risk in the general population. RESULTS: Of 491 TCS (median age at assessment, 38.2 years; range, 18.7-68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P= .006) and body mass index of 25 to <30 kg/m2 (OR, 2.08; P= .011) or ≥30 kg/m2 (OR, 2.36; P= .005) compared with <25 kg/m2. TCS with ≥2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P= .09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P= .07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ≥2 AHOs (65% vs 51%; P= .003), to take medications for hypercholesterolemia (20.1% vs 6.0%; P<.001) or hypertension (18.5% vs 10.6%; P= .013), and to report erectile dysfunction (19.6% vs 11.9%; P= .018) or peripheral neuropathy (30.7% vs 22.5%; P= .041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P= .07) or anxiety/depression (14.8% vs 9.3%; P= .06) was observed. CONCLUSIONS: At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients.

Terapia de reemplazo hormonal y enfermedad cardiovascular en el hombre adulto hipogonádico / Hormone replacement therapy and cardiovascular disease in the hypogonadal adult men

RESUMEN El diagnóstico de hipogonadismo requiere de la presencia de síntomas y signos sugestivos de deficiencia de testosterona asociado a la confirmación por estudios de laboratorio de valores de testosterona por debajo del valor normal. Se ha descrito un aumento en la prescripción de la terapia androgénica en el hipoandrogenismo asociado con la edad, y existe preocupación sobre los potenciales efectos adversos en especial a nivel cardiovascular relacionados con la misma. Los mecanismos fisiopatológicos propuestos en relación a los posibles efectos adversos de la testosterona sobre el sistema cardiovascular incluyen: aumento de la expresión de receptor para tromboxano A2 (TXA2), aumento de la expresión vascular en células endoteliales de la molécula de adhesión vascular 1 (VCAM1), estimulación de la eritropoyesis con el desarrollo de policitemia, como también aumento de la incidencia de síndrome apnea del sueño. Pero por otra parte, existe evidencia de que el hipogonadismo no tratado se asocia a aumento de enfermedad cardiovascular y mortalidad. Se sugiere considerar la administración de TRH en pacientes con hipogonadismo sintomático, tomando en cuenta los riesgos y beneficios asociados a la misma y con precaución en su indicación en los pacientes más frágiles y con alto riesgo cardiovascular.

ABSTRACT The diagnosis of hypogonadism requires of the presence of symptoms and signs suggestive of testosterone deficiency associated with confirmation by laboratory studies of testosterone below the normal value. It has been described an increase in the prescription of androgenic therapy in late onset hypogonadism (associated with aging) and there is concern of its potential adverse effects, especially on cardiovascular events. The proposed physiopathological mechanisms, related to the adverse effects of testosterone on the cardiovascular system include: increased expression of thromboxane A2 receptors (TXA2), increased expression of vascular cell adhesion molecule-1 (VCAM1), stimulation of erythropoiesis with the development of polycythemia, as well as an increase in the incidence of sleep apnea syndrome. On the other hand, evidence exists on the association of not treated hypogonadism with an increase in cardiovascular disease and mortality. It is suggested to consider the use of testosterone therapy in patients with symptomatic hypogonadism, always taking into account the possible risks and benefits associated with its use and being careful on its indication in fragile patients with high cardiovascular risk.

Recovery from hypogonadism and male health in adult allogeneic stem cell transplantation.

OBJECTIVE: There is a substantial lack of data about men`s health in adult allogeneic stem cell transplantation. METHODS: We conducted prospective unicentric non-interventional clinical study on men's health with a follow-up time of 1 year. RESULTS: Between 11/2013 and 12/2015, we were able to include 27 patients. AML was the most frequent underlying disease (25.9%), and we mainly used intermediate intense conditioning protocols (77.8%). Erectile dysfunction, loss of libido, and loss of efficiency were the most frequent symptoms of hypogonadism. At inclusion of the study, hypogonadism was already frequent. Primary hypogonadism was found in eight cases (29.6%) and secondary hypogonadism in one case (3.7%). We did not observe hypogonadism 6 months after inpatient treatment anymore, but there might still be the impairment of fertility because of still rising FSH levels at the end of the observation period. There were no significant associations of hypogonadism with myeloablative conditioning or kind of donor. Interestingly, there is a significant association with nicotine abuse (P = .049). CONCLUSIONS: On the whole, male hypogonadism was found in one-third of the patients who underwent allogeneic stem cell transplantation.

High risk of hypogonadism in young male cancer survivors.

OBJECTIVE: Cancer and its treatment in childhood and young adulthood can cause hypogonadism, leading to increased risk of long-term morbidity and mortality. The aim of this study was to evaluate the risk of presenting with biochemical signs of hypogonadism in testicular cancer survivors (TCS) and male childhood cancer survivors (CCS) in relation to the type of treatment given. DESIGN: Case-control study. PATIENTS: Ninety-two TCS, 125 CCS (mean age 40 and median age 34 years, respectively; mean follow-up time 9.2 and 24 years, respectively) and a corresponding number of age-matched controls. MEASUREMENTS: Fasting morning blood samples were analysed for total testosterone (TT), follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The odds ratios (OR) for hypogonadism, defined as primary, secondary, compensated or ongoing androgen replacement, were calculated for TCS and CCS and for subgroups defined by diagnosis and treatment. RESULTS: Hypogonadism was found in 26% of CCS and 36% of TCS, respectively (OR: 2.1, P = .025 and OR = 2.3, P = .021). Among CCS, the OR was further increased in those given testicular irradiation (OR = 28, P = .004). Radiotherapy other than cranial or testicular irradiation plus chemotherapy, or cranial irradiation without chemotherapy, associated also with increased ORs (OR = 3.7, P = .013, and OR = 4.4, P = .038, respectively). Among TCS, those receiving >4 cycles of cisplatin-based chemotherapy had OR = 17, P = .015. CONCLUSIONS: Biochemical signs of testosterone deficiency are recognized as markers of decreased life expectancy. Thus, the risk of hypogonadism in TCS and CCS should be recognized and emphasizes the need of long-term follow-up for these men.

Long-Term Follow-Up of Primary Medical Versus Surgical Treatment of Prolactinomas in Men: Effects on Hyperprolactinemia, Hypogonadism, and Bone Health.

OBJECTIVE: In men with prolactinomas, impaired bone density is the principle consequence of hyperprolactinemia-induced hypogonadism. Although dopamine agonists (DAs) are the first-line approach in prolactinomas, surgery can be considered in selected cases. In this study, we aimed to investigate the long-term control of hyperprolactinemia, hypogonadism, and bone health comparing primary medical and surgical therapy in men who had not had prior DA treatment. METHODS: This is a retrospective case-note study of 44 consecutive men with prolactinomas and no prior DAs managed in a single tertiary referral center. Clinical, biochemical, and radiologic response to the first-line approach were analyzed in the 2 cohorts. RESULTS: Mean age at diagnosis was 47 years (range, 22-78 years). The prevalence of hypogonadism was 86%, and 27% of patients had pathologic bone density at baseline. The primary therapeutic strategy was surgery for 34% and DAs for 66% of patients. Median long-term follow-up was 63 months (range, 17-238 months). Long-term control of hyperprolactinemia required DAs in 53% of patients with primary surgical therapy, versus 90% of patients with primary medical therapy (P = 0.02). Hypogonadism was controlled in 73% of patients. The prevalence of patients with pathologic bone density was 37% at last follow-up, with no differences between the 2 therapeutic cohorts (P = 0.48). CONCLUSIONS: Despite control of hyperprolactinemia and hypogonadism in most patients independent of the primary treatment modality, the prevalence of impaired bone health status remains high, and osteodensitometry should be recommended.

Gonadal status in long-term male survivors of childhood cancer.

PURPOSE: To evaluate the prevalence of gonadal dysfunction and the associated risk factors in a cohort of male childhood cancer survivors (CCS). METHODS: Gonadal function was evaluated measuring FSH, LH, inhibin B and total testosterone levels. Patients with total testosterone <3 ng/dl were considered to have hypogonadism. Patients with FSH >10 UI/l and inhibin B <100 pg/ml were considered to have spermatogenesis damage (SD). To assess the impact of risk factors, we estimated crude and adjusted OR performing logistic regression models. RESULTS: One hundred and ninety-nine male CCS were enrolled; the median follow-up time was 14.01 years. SD was diagnosed in 68 patients, 16 CCS had primary hypogonadism, and 13 had central hypogonadism. The prevalence of gonadal dysfunction (SD or primary hypogonadism) was 45 %, similar in the three considered periods of pediatric cancer diagnosis (1985-1989, 1990-1999, >2000). The adjusted risk of gonadal dysfunction was higher in patients treated with radiotherapy (OR = 8.72; 95 % CI 3.94-19.30) and in those exposed to both alkylating and platinum-derived agents (OR = 9.22; 95 % CI 2.17-39.23). Sarcomas were the cancer diagnosis associated with the higher risk of gonadal dysfunction (OR = 3.69; 95 % CI 1.11-12.22). An extremely high rate of gonadal dysfunction was detected in patients who underwent hematopoietic stem cell transplantation and/or total body irradiation. CONCLUSIONS: Gonadal dysfunction still remains a significant late effect of anticancer therapies; thus, it is mandatory to inform patients (and parents) about this risk, and semen cryopreservation should be offered to all boys who are able to produce semen.

Testosterone and mortality.

Epidemiological studies have found that men with low or low normal endogenous testosterone are at an increased risk of mortality than those with higher levels. Cardiovascular disease accounts for the greater proportion of deaths in those with low testosterone. Cancer and respiratory deaths in some of the studies are also significantly more prevalent. Disease-specific studies have identified that there are higher mortality rates in men with cardiovascular, respiratory and renal diseases, type 2 diabetes and cancer with low testosterone. Obesity, metabolic syndrome, type 2 diabetes, cardiovascular disease and inflammatory disorders are all associated with an increased prevalence of testosterone deficiency. Two major questions that arise from these findings are (1) is testosterone deficiency directly involved in the pathogenesis of these conditions and/or a contributory factor impairing the body's natural defences or is it merely a biomarker of ill health and the severity of underlying disease process? (2) Does testosterone replacement therapy retard disease progression and ultimately enhance the clinical prognosis and survival? This review will discuss the current state of knowledge and discuss whether or not there are any answers to either of these questions. There is convincing evidence that low testosterone is a biomarker for disease severity and mortality. Testosterone deficiency is associated with adverse effects on certain cardiovascular risk factors that when combined could potentially promote atherosclerosis. The issue of whether or not testosterone replacement therapy improves outcomes is controversial. Two retrospective studies in men with diagnosed hypogonadism with or without type 2 diabetes have reported significantly improved survival.

Late-onset hypogonadism and mortality in aging men.

CONTEXT: Late-onset hypogonadism (LOH) has recently been defined as a syndrome in middle-aged and elderly men reporting sexual symptoms in the presence of low T. The natural history of LOH, especially its relationship to mortality, is currently unknown. OBJECTIVE: The aim of this study was to clarify the associations between LOH, low T, and sexual symptoms with mortality in men. DESIGN, SETTING, AND PARTICIPANTS: Prospective data from the European Male Aging Study (EMAS) on 2599 community-dwelling men aged 40-79 years in eight European countries was used for this study. MAIN OUTCOME MEASURE(S): All-cause, cardiovascular, and cancer-related mortality was measured. RESULTS: One hundred forty-seven men died during a median follow-up of 4.3 years. Fifty-five men (2.1%) were identified as having LOH (31 moderate and 24 severe). After adjusting for age, center, body mass index (BMI), current smoking, and poor general health, compared with men without LOH, those with severe LOH had a 5-fold [hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.7, 11.4] higher risk of all-cause mortality. Compared with eugonadal men, the multivariable-adjusted risk of mortality was 2-fold higher in those with T less than 8 nmol/L (irrespective of symptoms; HR 2.3; 95% CI 1.2, 4.2) and 3-fold higher in those with three sexual symptoms (irrespective of serum T; compared with asymptomatic men; HR 3.2; 95% CI 1.8, 5.8). Similar risks were observed for cardiovascular mortality. CONCLUSIONS: Severe LOH is associated with substantially higher risks of all-cause and cardiovascular mortality, to which both the level of T and the presence of sexual symptoms contribute independently. Detecting low T in men presenting with sexual symptoms offers an opportunity to identify a small subgroup of aging men at particularly high risk of dying.

Testosterone replacement therapy following the diagnosis of prostate cancer: outcomes and utilization trends.

INTRODUCTION: Late-onset hypogonadism may impair quality of life and contribute to metabolic and cardiovascular comorbidity in aging men. Testosterone replacement therapy is effective in treating hypogonadism. However, for the millions of men with a history of prostate cancer, exogenous testosterone has long been considered contraindicated, even though little data in such men are available. Clarification of this safety issue could allow treatment to be considered for a sizeable segment of the aging male population. AIM: The aim of this study is to examine population-based utilization and impact of testosterone replacement therapy in men with prostate cancer. METHODS: Using linked Surveillance, Epidemiology, and End Results-Medicare data, we identified 149,354 men diagnosed with prostate cancer from 1992 to 2007. Of those, 1181 (0.79%) men received exogenous testosterone following their cancer diagnosis. We used propensity scoring analysis to examine the effect of testosterone replacement on the use of salvage hormone therapy and overall and prostate cancer-specific mortality. MAIN OUTCOME MEASURES: We assessed overall mortality, cancer-specific mortality, and the use of salvage hormone therapy. RESULTS: Following prostate cancer diagnosis, testosterone replacement was directly related to income and educational status and inversely related to age (all P < 0.001). Men undergoing radical prostatectomy and men with well-differentiated tumors were more likely to receive testosterone (all P < 0.001). On adjusted analysis, testosterone replacement therapy was not associated with overall or cancer-specific mortality or with the use of salvage hormone therapy. CONCLUSIONS: In this population-based observational study of testosterone replacement therapy in men with a history of prostate cancer, treatment was not associated with increased overall or cancer-specific mortality. These findings suggest testosterone replacement therapy may be considered in men with a history of prostate cancer, but confirmatory prospective studies are needed.

Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study.

OBJECTIVE: To verify whether hypogonadism represents a risk factor for cardiovascular (CV) morbidity and mortality and to verify whether testosterone replacement therapy (TRT) improves CV parameters in subjects with known CV diseases (CVDs). DESIGN: Meta-analysis. METHODS: An extensive Medline search was performed using the following words 'testosterone, CVD, and males'. The search was restricted to data from January 1, 1969, up to January 1, 2011. RESULTS: Of the 1178 retrieved articles, 70 were included in the study. Among cross-sectional studies, patients with CVD have significantly lower testosterone and higher 17-ß estradiol (E(2)) levels. Conversely, no difference was observed for DHEAS. The association between low testosterone and high E(2) levels with CVD was confirmed in a logistic regression model, after adjusting for age and body mass index (hazard ratio (HR)=0.763 (0.744-0.783) and HR=1.015 (1.014-1.017), respectively, for each increment of total testosterone and E(2) levels; both P<0.0001). Longitudinal studies showed that baseline testosterone level was significantly lower among patients with incident overall- and CV-related mortality, in comparison with controls. Conversely, we did not observe any difference in the baseline testosterone and E(2) levels between case and controls for incident CVD. Finally, TRT was positively associated with a significant increase in treadmill test duration and time to 1 mm ST segment depression. CONCLUSIONS: Lower testosterone and higher E(2) levels correlate with increased risk of CVD and CV mortality. TRT in hypogonadism moderates metabolic components associated with CV risk. Whether low testosterone is just an association with CV risk, or an actual cause-effect relationship, awaits further studies.

Mortality and reduced growth hormone secretion.

BACKGROUND: Data regarding the mortality rates of patients with growth hormone deficiency (GHD), whether or not treated with growth hormone (GH), are limited, but an increased mortality rate among hypopituitary patients compared with the general population has been documented. Cardiovascular disease has been suggested as a primary cause of death, whereas cancer statistics might be influenced by the number of malignancies causing the pituitary disease. Furthermore, differences in mortality rates in females and males have been reported. METHODS: Epidemiological studies of mortality in hypopituitary and GHD patients were identified and reviewed. RESULTS: Most studies showed an increased mortality rate in hypopituitary and GHD patients and an increased mortality among female compared with male patients. There is a possibility that differences between patients with adult-onset and childhood-onset GHD might also exist. Two studies showed a normal mortality rate in GHD patients treated with GH compared with the general population. CONCLUSIONS: Although an increased mortality rate in hypopituitary patients is well documented, further research is needed to provide more reliable estimates of the actual causes. Caution should be taken in the interpretation of results regarding mortality and GH treatment due to the limited amount of data and the limitations of the study designs.