Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes.

BACKGROUND: Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. METHODS: We searched the international pharmacovigilance database VigiBase for men (n=6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone. RESULTS: Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n=168) and/or TdP (n=68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio=1.4-4.7; P<0.05) with aLQTS, TdP, or sudden death. The minimum and median times to sudden death were 0.25 and 92 days, respectively. The androgen receptor antagonist enzalutamide was associated with more deaths (5430/31 896 [17%]; P<0.0001) than other ADT used for prostate cancer (4208/52 089 [8.1%]). In induced pluripotent stem cells, acute and chronic enzalutamide (25µM) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5Hz; 429.7±27.1 (control) versus 982.4±33.2 (acute, P<0.001) and 1062.3±28.9ms (chronic; P<0.001), and generated afterdepolarizations and/or triggered activity in drug-treated cells (11/20 acutely and 8/15 chronically). Enzalutamide acutely and chronically inhibited delayed rectifier potassium current, and chronically enhanced late sodium current. Dihydrotestosterone (30nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells. CONCLUSION: QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.

Late-onset hypogonadism: Reductio ad absurdum of the cardiovascular risk-benefit of testosterone replacement therapy.

BACKGROUND: Low testosterone (T) level is considered a marker of poor cardiovascular health. Ten years ago, the Testosterone in Older Men with Mobility Limitations (TOM) trial was discontinued due to a higher number of adverse events in men receiving T compared with placebo. Since then, several studies have investigated the risks of T replacement therapy (TRT) in late-onset hypogonadism (LOH). OBJECTIVE: To review the mechanism by which TRT could damage the cardiovascular system. MATERIALS AND METHODS: Comprehensive literature search of recent clinical and experimental studies. RESULTS: The mechanisms of T-mediated coronary vasodilation were reviewed with emphasis on calcium-activated and ATP-sensitive potassium ion channels. We showed how T regulates endothelial nitric oxide synthase (eNOS) and phosphoinositide 3-kinase/protein kinase B/eNOS signaling pathways in vessel walls and its direct effects on cardiomyocytes via ß1-adrenergic and ryanodine receptors and provided data on myocardial infarction and heart failure. Vascular smooth muscle senescence could be explained by the modulation of growth factors, matrix metalloproteinase-2, and angiotensin II by T. Furthermore, leukocyte trafficking, facilitated by changes in TNF-α, could explain some of the effects of T on atheromatous plaques. Conflicting data on prothrombotic risk linked to platelet aggregation inhibition via NO-triggered arachidonate synthesis or increased aggregability due to enhanced thromboxane A in human platelets provide evidence regarding the hypotheses on plaque maturation and rupture risk. The effects of T on cardiac electrophysiology and oxygen delivery were also reviewed. DISCUSSION: The effects of TRT on the cardiovascular system are complex. Although molecular studies suggest a potential benefit, several clinical observations reveal neutral or occasionally detrimental effects, mostly due to confounding factors. CONCLUSIONS: Attempts to demonstrate that TRT damages the cardiovascular system via systematic analysis of the putative mechanisms led to the contradiction of the initial hypothesis. Current evidence indicates that TRT is safe once other comorbidities are addressed.

Rates of hypogonadism forms in Klinefelter patients undergoing testicular sperm extraction: A multicenter cross-sectional study.

INTRODUCTION AND OBJECTIVES: Adult patients with Klinefelter syndrome (KS) may present with testicular volume loss and a decrease in circulating testosterone (T) levels. However, the actual rate of hypogonadism in adult KS men is unknown. We aimed to (a) assess the prevalence of different forms of hypogonadism in a cohort of KS patients with non-obstructive azoospermia (NOA); and (b) investigate potential preoperative predictor of positive sperm retrieval (SR) at surgery in the same cohort of men. METHODS: Complete data from 103 KS men with NOA who underwent testicular sperm extraction (TESE) between 2008 and 2019 at five centers were analyzed. Comorbidities were scored with the Charlson Comorbidity Index (CCI). Patients were categorized into four groups of hypogonadism as follows: eugonadism [normal total T (tT) (≥3.03 ng/mL) and normal luteinizing hormone (LH) (≤9.4 mUI/mL)], secondary hypogonadism [low tT (≤3.03 ng/mL) and low/normal LH (≤9.4 mUI/mL)], primary hypogonadism [low tT (≤3.03 ng/mL) and elevated LH (≥9.4 mUI/mL)], and compensated hypogonadism [normal tT (≥3.03 ng/mL) and elevated LH (≥9.4 mUI/mL)]. Descriptive statistics tested the association between clinical characteristics and laboratory values among the four groups. RESULTS: Median (IQR) patients age was 32 (24, 37) years. Baseline follicle-stimulating hormone and tT levels were 29.5 (19.9, 40.9) mUI/mL and 3.8 (2.5, 11.0) ng/mL, respectively. Eugonadism, primary hypogonadism, and compensated hypogonadism were found in 16 (15.6%), 34 (33.0%), and 53 (51.4%) men, respectively. No patients had secondary hypogonadism. Positive SR rate at TESE was 21.4% (22 patients); of 22, 15 (68.2%) patients underwent assisted reproductive technology and five (22.7%) ended in live birth children. Patients' age, BMI, CCI, FSH levels, and positive SR rates were comparable among hypogonadism groups. No preoperative parameters were associated with positive SR at logistic regressions analysis. CONCLUSIONS: Findings from this cross-sectional study showed that 15.6% of adult KS men have normal tT values at presentation in the real-life setting. Most KS patients presented with either compensated or primary hypogonadism. Sperm retrieval rates were not associated with different forms of hypogonadism.

Late-onset Hypogonadism: Bone health.

BACKGROUND: Bone health is underdiagnosed and undermanaged in men. Bone loss occurs in men with hypogonadism and in aging men. Thus, patients with a diagnosis of late-onset hypogonadism (LOH) are at risk of osteoporosis and osteoporotic fractures. OBJECTIVES: To provide an update on research data and clinical implications regarding bone health in men with LOH by reviewing literature articles on this issue. MATERIALS AND METHODS: A thorough search of listed publications in PubMed on bone health in older men with hypogonadism was performed, and other articles derived from these publications were further identified. RESULTS: Late-onset Hypogonadism may be associated with reduced bone mineral density (BMD). In a pathophysiological perspective, the detrimental effects of testosterone (T) deficiency on BMD are partly ascribed to relative estrogen deficiency and both serum T and serum estradiol (E2) need to be above 200 ng/dL and 20 pg/mL to prevent bone loss. The effects of exogenous T on BMD are controversial, but most of the studies confirm that testosterone replacement therapy (TRT) increases BMD and prevents further bone loss in men with hypogonadism. No data are available on TRT and the prevention of fractures. DISCUSSION AND CONCLUSION: In men with documented LOH, a specific clinical workup should be addressed to the diagnosis of osteoporosis in order to program subsequent follow-up and consider specific bone active therapy. TRT should be started according to guidelines of male hypogonadism while keeping in mind that it may also have positive effects also on bone health in men with LOH.

Late-onset hypogonadism: Prostate safety.

BACKGROUND: There have always been concerns regarding testosterone replacement therapy and prostate safety because of the central role of testosterone in prostate tissue. Even though there is a body of evidence supporting that the benefits of testosterone replacement therapy outbalance the risks of prostate disease, this matter is still debatable and represents a common concern among testosterone prescribers. OBJECTIVES: The aim of this article was to review the influence of testosterone on prostate pathophysiology and discuss the potential impact of testosterone replacement therapy on the most common prostate pathologies, including benign prostatic hyperplasia and prostate cancer. MATERIALS AND METHODS: We have performed an extensive PubMed review of the literature examining the effects of testosterone replacement therapy on the prostate and its most common affections, especially in terms of safety. RESULTS: Testosterone replacement therapy has been shown to improve components of metabolic syndrome and decrease prostate inflammation, which is related to the worsening of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia. Studies evaluating the link between testosterone replacement therapy and benign prostatic hyperplasia/LUTS have mostly demonstrated no change in symptom scores and even some benefits. There are a significant number of studies demonstrating the safety of testosterone replacement therapy in individuals with late-onset hypogonadism and a history of prostate cancer. The most recently published guidelines have already acknowledged this fact and do not recommend against T treatment in this population, particularly in non-high-risk disease. CONCLUSION: Testosterone replacement therapy could be considered for most men with late-onset hypogonadism regardless of their history of prostate disease. However, a discussion about the risks and benefits of testosterone replacement therapy is always advised, especially in men with prostate cancer. Appropriate monitoring is mandatory.

Late-onset hypogonadism: a concept comes of age.

The term Late-onset hypogonadism (LOH) was coined in 2002 and defined as a disease entity in the ISA, ISSAM, EAU, EAA and ASA endorsed Recommendations for Investigation, Treatment and Monitoring of LOH (2005 and 2008) as 'a clinical and biochemical syndrome associated with advancing age, characterized by symptoms and a deficiency in serum testosterone (T)'. LOH was classified as a combined primary and secondary hypogonadism since the endocrine capacity of the testes and the pituitary are impaired. Symptoms of LOH include loss of libido, erectile dysfunction, loss of muscle mass, increased body fat, anemia, osteoporosis, depressed mood, decreased vitality, sweating, and hot flushes. Since these symptoms may also have origins other than LOH, exclusion of other disease entities and subnormal serum T levels are considered prerequisites for the diagnosis and possible treatment of LOH. However, during following years these guidelines were often neglected and, especially in the USA, indiscriminate prescribing of T was widely practised so that the US FDA warned against such irresponsible behavior. In Europe, T prescribing remained largely restricted to LOH as defined above. Nevertheless, a discussion started whether LOH really exists or is only a consequence of age-related comorbidities. Numerous studies have helped to clarify the situation, in particular, the European Male Aging Study (EMAS) and the US-initiated 7 T trials. Consequently, the newest US Endocrine Society Practice Guideline on T treatment (2018) includes advanced age as a cause of organic hypogonadism and recommends that 'in men >65 years who have symptoms or conditions suggestive of T deficiency … and consistently and unequivocally low morning T concentrations we suggest that clinicians offer T therapy on an individualised basis after explicit discussion of the potential risks and benefits'. Thus, the concept of LOH as conceived two decades ago has weathered criticism and survived the times.

Hormone-related diseases and prostate cancer: An English national record linkage study.

Insulin-like growth factor-I (IGF-I) and testosterone may be related to prostate cancer risk. Acromegaly is associated with clinically high IGF-I concentrations. Klinefelter's syndrome, testicular hypofunction and hypopituitarism are associated with clinically low testosterone concentrations. We aimed to investigate whether diagnosis with these conditions was associated with subsequent prostate cancer diagnosis and mortality. We used linked English national Hospital Episode Statistics and mortality data from 1999 to 2017 to construct and follow-up cohorts of men aged ≥35 years diagnosed with (i) acromegaly (n = 2,495) and (ii) hypogonadal-associated diseases (n = 18,763): Klinefelter's syndrome (n = 1,992), testicular hypofunction (n = 8,086) and hypopituitarism (n = 10,331). We estimated adjusted hazard ratios (HRs) and confidence intervals (CIs) for prostate cancer diagnosis and death using Cox regression in comparison with an unexposed reference cohort of 4.3 million men, who were admitted to hospital for a range of minor surgeries and conditions (n observed cases = 130,000, n prostate cancer deaths = 30,000). For men diagnosed with acromegaly, HR for prostate cancer diagnosis was 1.33 (95% CI 1.09-1.63; p = 0.005; n observed cases = 96), HR for prostate cancer death was 1.44 (95% CI 0.92-2.26; p = 0.11; n deaths = 19). Diagnosis with Klinefelter's syndrome was associated with a lower prostate cancer risk (HR = 0.58, 95% CI 0.37-0.91; p = 0.02; n observed cases = 19) and hypopituitarism was associated with a reduction in prostate cancer death (HR = 0.53, 95% CI 0.35-0.79; p = 0.002; n deaths = 23). These results support the hypothesised roles of IGF-I and testosterone in prostate cancer development and/or progression. These findings are important because they provide insight into prostate cancer aetiology.

Metabolic Syndrome in Male Hypogonadism.

Metabolic syndrome (MetS) and hypogonadism (HG) are frequently comorbid. In this review, we summarize interconnections between the construct of MetS and the presence of HG, as well as the effect of specific treatments for each condition on this association. Data from meta-analytic studies suggest a bidirectional pathogenic relationship. In fact, reduced T (-2.21 [-2.43 to -1.98] nmol/L) at baseline predicts incident MetS. On the other hand, MetS at study entry increases the risk of developing HG (OR 2.46 [1.77-3.42]). The bidirectional pathogenic link between MetS and HG is further confirmed by the fact that treating MetS with insulin sensitizer is associated with an increase in T. In addition, a huge effect on increasing T is found in obese men undergoing procedures for losing weight, with more dramatic results obtained after bariatric surgery than after low calorie diet (increase in T 8.73 [6.51-10.95] nmol/L and 2.87 [1.68-4.07] nmol/L, respectively, according to a recent meta-analysis). On the other hand, there is evidence of an improvement in several metabolic derangements characterizing MetS in subjects treated with T. However, the latter results are still not conclusive and need further evidence from randomized clinical trials.

NASH in Nondiabetic Endocrine Disorders.

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease, including hepatic steatosis, inflammation, and fibrosis. NAFLD carries the risk of progression to cirrhosis with its associated complications and hepatocellular carcinoma. It is now the most common liver disease in the Western world and its prevalence is increasing. While the association between NAFLD and type 2 diabetes has been well documented, there is significantly less understanding of the pathophysiology and progression of NAFLD in patients with other endocrine disorders affecting metabolism in various ways. Some of the more common endocrine disorders such as polycystic ovarian syndrome, growth hormone deficiency, hypothyroidism, and hypogonadism are known in clinical practice to be associated with NAFLD. Medications that alter the endocrine system such as tamoxifen and adrenal steroids have also been attributed to significant NAFLD. The key to management of NAFLD at this time are dietary changes and exercise to achieve weight loss. Unfortunately, a large proportion of the patients with these endocrine disorders are unable to achieve either. This review aims to examine and summarize the current published literature that have evaluated the association between NAFLD and the above endocrine disorders and potential therapeutic interventions in each case.

Primary, secondary and compensated hypogonadism: a novel risk stratification for infertile men.

Recently, the cohort of men from the European Male Ageing Study has been stratified into different categories distinguishing primary, secondary and compensated hypogonadism. A similar classification has not yet been applied to the infertile population. We performed a cross-sectional study enrolling 786 consecutive Caucasian-European infertile men segregated into eugonadal [normal serum total testosterone (≥3.03 ng/mL) and normal luteinizing hormone (≤9.4 mU/mL)], secondary (low total testosterone, low/normal luteinizing hormone), primary (low total testosterone, elevated luteinizing hormone) and compensated hypogonadism (normal total testosterone; elevated luteinizing hormone). In this cross-sectional study, logistic regression models tested the association between semen parameters, clinical characteristics and the defined gonadal status. Eugonadism, secondary, primary and compensated hypogonadism were found in 80, 15, 2, and 3% of men respectively. Secondary hypogonadal men were at highest risk for obesity [OR (95% CI): 3.48 (1.98-6.01)]. Primary hypogonadal men were those at highest risk for azoospermia [24.54 (6.39-161.39)] and testicular volume <15 mL [12.80 (3.40-83.26)]. Compensated had a similar profile to primary hypogonadal men, while their risk of azoospermia [5.31 (2.25-13.10)] and small testicular volume [8.04 (3.17-24.66)] was lower. The risk of small testicular volume [1.52 (1.01-2.33)] and azoospermia [1.76 (1.09-2.82)] was increased, although in a milder fashion, in secondary hypogonadal men as well. Overall, primary and compensated hypogonadism depicted the worst clinical picture in terms of impaired fertility. Although not specifically designed for infertile men, European Male Ageing Study categories might serve as a clinical stratification tool even in this setting.

European Association of Urology Position Statement on the Role of the Urologist in the Management of Male Hypogonadism and Testosterone Therapy.

Testosterone is a crucial sex hormone important for the health and development of men of all ages. It plays a role in the integrity and maintaining the function of several systems and organs. Testosterone deficiency is linked to a number of signs and symptoms potentially affecting every man in his complexity and masculinity, and is therefore of strong urological interest. For this reason, urologists should attach importance to the need for knowledge, vocational education, and training in this specific area.

Fatigue and related comorbidities, active component, U.S. Armed Forces, 2007-2016.

Fatigue is a common complaint in the civilian population and may be a presenting symptom of more serious physical and mental disorders. Data from the Defense Medical Surveillance System (DMSS) were utilized to characterize the incidence and burden of fatigue in active component military members from 1 January 2007 through 31 December 2016. A subanalysis of 3 years within this surveillance period (2012-2014) was also conducted to assess the burden of comorbidities related to incident fatigue and the strength of the association between fatigue and selected comorbidities. The study identified 211,213 incident cases of fatigue with an overall incidence rate of 18.1 per 1,000 person-years between 2007 and 2016. Mental disorders and musculoskeletal disease accounted for about 35% of all medical encounters and about 40% of all hospital days within a year for those diagnosed with fatigue in 2013. The adjusted odds ratio for fatigue was highest in those with male hypogonadism, thyroid disorder, and sleep problems. These results show that fatigue is a common diagnosis with high incidence and burden among active component U.S. military. By focusing on the conditions that frequently occur and are highly associated with fatigue, more rapid diagnosis and treatment of the underlying cause of service member fatigue is possible.

Enclomiphene citrate for the treatment of secondary male hypogonadism.

INTRODUCTION: Hypogonadism is a growing concern in an aging male population. Historically treated using exogenous testosterone, concerns about possible adverse effects of testosterone have led physicians to seek alternative treatment approaches. AREAS COVERED: Enclomiphene citrate is the trans isomer of clomiphene citrate, a non-steroidal estrogen receptor antagonist that is FDA-approved for the treatment of ovarian dysfunction in women. Clomiphene citrate has also been used off-label for many years to treat secondary male hypogonadism, particularly in the setting of male infertility. Here we review the literature examining the efficacy and safety of enclomiphene citrate in the setting of androgen deficiency. EXPERT OPINION: Initial results support the conclusion that enclomiphene citrate increases serum testosterone levels by raising luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, without negatively impacting semen parameters. The ability to treat testosterone deficiency in men while maintaining fertility supports a role for enclomiphene citrate in the treatment of men in whom testosterone therapy is not a suitable option.

The reproductive health indices and sex hormone levels in middle-aged and elderly Chinese men.

OBJECTIVE: The aim of this study was to analyze the age-related recession trajectory of reproductive health indices in middle-aged and elderly Chinese men. METHODS: A population-based cross-sectional study was conducted in Jiashan County, Zhejiang in 2012. Healthy men between 40 and 80 years of age were considered eligible for the study. Physical examination and the sex hormones were measured. The subjects were assessed based on the 5-item version of the International Index of Erectile Function (IIEF-5) for Erectile Dysfunction (ED), and Aging Males' Symptoms (AMS) scale for Symptomatic Late-Onset Hypogonadism (SLOH). RESULTS: TG showed a decrease at age 60 years. Testis volume and TT did not show significant difference among the four age groups; cFT began to decrease at age 50 years and Bio-T decreased faster at age 50 years. SHBG and LH increased faster at age 50 and 70 years, respectively. IIEF5 score decrease faster at age 60 years. AMS scores increased faster at age 70 years. With the increase in age, the symptoms of ED and SLOH became severer. CONCLUSION: Different indices on reproductive health of men showed turning points at different ages. At first, androgenic sex hormones decreased faster, and then erectile dysfunction got severer, and the last overall male syndromes declined.

Obesity and late-onset hypogonadism.

Obesity and male hypogonadism (HG) are often associated, as demonstrated in all cross-sectional studies. Prospective studies have indicated that i) having HG at baseline increases the risk of visceral obesity (and metabolic syndrome) and that ii) obesity induces incident HG. Hence, there is a bidirectional relationship between the two conditions. This is the main topic of this review, along with some pathogenic considerations. Meta-analysis of intervention studies indicates that treating obesity is a very efficient treatment for obesity-induced HG. The mechanism by which obesity induces HG has not yet been completely understood, but dietary-induced hypothalamic inflammation, along with a decreased GnRH release, is plausible. Among patients seeking medical care for obesity, the proportion of HG is relatively high. The prevalence of obesity among patients referring for sexual dysfunction is also elevated. Hence, in symptomatic, obese, hypogonadal subjects, testosterone supplementation (TS) can be considered. Whereas long-term uncontrolled register studies suggest that TS could decrease weight, analysis of controlled studies only support a parallel increase in lean mass and decrease in fat mass, with a resulting null effect on weight. Considering that T induces an increase in muscle mass, it is conceivable that the amount of activity obese people can undertake after TS will increase, allowing a closer adherence to physical exercise programs. Some studies, here meta-analyzed, support this concept.

Testosterone Replacement in Androgen-Deficient Men With Ejaculatory Dysfunction: A Randomized Controlled Trial.

CONTEXT: Low T levels have been associated with ejaculatory dysfunction (EjD) in cross-sectional studies; however, the efficacy of T replacement in improving EjD has not been studied in a randomized controlled trial. OBJECTIVE: To evaluate the efficacy of T replacement in androgen-deficient men with EjD. DESIGN: A multicenter, double-blind, randomized, placebo-controlled, 16-week trial with T solution 2% versus placebo. SETTING: Medical centers in the United States, Canada, and Mexico. PATIENTS OR OTHER PARTICIPANTS: Seventy-six men with one or more EjD symptoms, including delayed ejaculation, anejaculation, reduced ejaculate volume, and/or reduced force of ejaculation, and two total T levels <300 ng/dL (<10.41 nmol/L) measured with liquid chromatography tandem mass spectrometry. INTERVENTIONS: Sixty milligrams of T solution 2% or placebo applied to the axillae for 16 weeks. MAIN OUTCOME MEASURES: The primary outcome was a change in the score of the three-item Male Sexual Health Questionnaire-Ejaculatory Dysfunction-Short Form (MSHQ-EjD-SF); secondary outcomes included measured ejaculate volume, scores of the bother/satisfaction item of the MSHQ-EjD-SF, the orgasmic function domain of the International Index of Erectile Function Questionnaire, and the sexual activity log. RESULTS: Seventy-six participants were randomized; 66 completed the study. Baseline demographic and clinical characteristics were comparable between the treatment arms. T replacement improved the MSHQ-EjD-SF score (mean score change, +3.1); however, this effect was not statistically different from placebo (mean score change, +2.5; P = .596). No differences were seen in any of the secondary outcomes or frequency of adverse events. CONCLUSION: T replacement was not associated with significant improvement in EjD in androgen-deficient men.

Male reproductive disorders, diseases, and costs of exposure to endocrine-disrupting chemicals in the European Union.

INTRODUCTION: Increasing evidence suggests that endocrine-disrupting chemicals (EDCs) contribute to male reproductive diseases and disorders. PURPOSE: To estimate the incidence/prevalence of selected male reproductive disorders/diseases and associated economic costs that can be reasonably attributed to specific EDC exposures in the European Union (EU). METHODS: An expert panel evaluated evidence for probability of causation using the Intergovernmental Panel on Climate Change weight-of-evidence characterization. Exposure-response relationships and reference levels were evaluated, and biomarker data were organized from carefully identified studies from the peer-reviewed literature to represent European exposure and approximate burden of disease as it occurred in 2010. The cost-of-illness estimation utilized multiple peer-reviewed sources. RESULTS: The expert panel identified low epidemiological and strong toxicological evidence for male infertility attributable to phthalate exposure, with a 40-69% probability of causing 618,000 additional assisted reproductive technology procedures, costing €4.71 billion annually. Low epidemiological and strong toxicological evidence was also identified for cryptorchidism due to prenatal polybrominated diphenyl ether exposure, resulting in a 40-69% probability that 4615 cases result, at a cost of €130 million (sensitivity analysis, €117-130 million). A much more modest (0-19%) probability of causation in testicular cancer by polybrominated diphenyl ethers was identified due to very low epidemiological and weak toxicological evidence, with 6830 potential cases annually and costs of €848 million annually (sensitivity analysis, €313-848 million). The panel assigned 40-69% probability of lower T concentrations in 55- to 64-year-old men due to phthalate exposure, with 24 800 associated deaths annually and lost economic productivity of €7.96 billion. CONCLUSIONS: EDCs may contribute substantially to male reproductive disorders and diseases, with nearly €15 billion annual associated costs in the EU. These estimates represent only a few EDCs for which there were sufficient epidemiological studies and those with the highest probability of causation. These public health costs should be considered as the EU contemplates regulatory action on EDCs.

Male hypogonadism and metabolic syndrome.

The role of androgens in cardiovascular disease is still controversial in men. In this study, we investigated metabolic disorders in Tunisian hypogonadal men compared with healthy controls. Forty hypogonadal men and 80 control subjects were enrolled. Patients with a history of pre-existing panhypopituitarism, thyroid dysfunction or inflammatory disease were excluded. Glycaemia, glycated haemoglobin (HbA1c), high-sensitive C-reactive protein (hsCRP), lipid profile, insulin, testosterone and gonadotrophins were measured. Insulin resistance was assessed by homoeostasis model assessment of insulin resistance (Homa IR). Waist circumference, body mass index and blood pressure were significantly higher in patients compared with controls. Glycemia, HbA1c, fasting serum insulin and Homa IR were significantly increased among hypogonadal men. In univariate analysis, testosterone levels were inversely correlated with body mass index, waist circumference, blood pressure, glycaemia, HbA1C, insulin, Homa IR and hsCRP. In multivariate analysis including all significant variables, initial testosterone level was the only independent risk factor for developing dyslipidaemia. With logistic regression, male hypogonadism was an independent risk factor for MS (P < 0.001). We conclude that low testosterone level plays a central role in the development of metabolic syndrome. Further prospective data are required to establish the causative link.

Serum 25-hydroxyvitamin D levels and testosterone deficiency in middle-aged Korean men: a cross-sectional study.

Previous studies have demonstrated that male hypogonadism is associated with a low level of vitamin D. However, no reports have investigated the effects of vitamin D on testosterone levels in Korean men. Our aim was to investigate whether testosterone levels are associated with serum vitamin D levels and whether seasonal variation exists. This cross-sectional study analyzed serum 25-hydroxyvitamin D [25(OH)D], total testosterone (TT), and free testosterone (FT) in 652 Korean men over 40 years of age who had undergone a comprehensive medical examination. The average age of the subjects was 56.7 ± 7.9 years, and the mean serum 25(OH)D, TT and FT levels were 21.23 ± 7.9 ng ml-1 , 4.70 ± 1.6 ng ml-1 , and 8.12 ± 3.3 pg ml-1 , respectively. In the multiple linear regression model, 25(OH)D showed positive association with TT (ß =0.137, P< 0.001) and FT (ß =0.103, P= 0.008). 25(OH)D and FT showed similar seasonal or monthly variation after adjustment for age. A vitamin D deficiency [25(OH)D < 20 ng ml-1 ] was associated with an increased risk of deficiencies of TT (<2.30 ng ml-1 ) (odds ratio [OR]: 2.65; 95% confidence interval [CI]: 1.21-5.78, P= 0.014) and FT (<6.50 pg ml-1 ) (OR: 1.44; 95% CI: 1.01-2.06 P= 0.048) after adjusting for age, season, body mass index, body composition, chronic disease, smoking, and alcohol use. In conclusion, we demonstrated a positive correlation between 25(OH)D and testosterone, which showed similar seasonal variation in Korean men.

Performance of Massachusetts Male Aging Study (MMAS) and androgen deficiency in the aging male (ADAM) questionnaires in the prediction of free testosterone in patients aged 40 years or older treated in outpatient regimen.

OBJECTIVE: At present, calculated free testosterone assessment is considered as the gold standard in diagnosing male hypogonadism. However, this assessment is not available for all the individuals diagnosed with decreased testicular function. The investigators of this study were, thus, prompted to evaluate whether the androgen deficiency in the aging male (ADAM) and the Massachusetts Male Ageing Study (MMAS) questionnaires could be used to replace biochemical parameters in the diagnosis for hypogonadism in men aged 40 years and above. METHODS: We evaluated 460 men, aged 40 years and above, all volunteers of a screening program for prostate cancer based at the Hospital de Clínicas of Porto Alegre. In this study, we assessed the efficiency of the ADAM and MMAS questionnaires in diagnosing Brazilian men with low levels of total, calculated free and bioavailable testosterone. RESULTS: The sensitivity of the ADAM questionnaire in diagnosing the calculated free testosterone was 73.6%, whereas specificity was 31.9%. ADAM could be used to properly classify our cohort into normal or hypogonadal individuals in 52.75% of the cases. The sensitivity of the MMAS questionnaire was 59.9%, whereas the specificity was 42.9%, resulting in a successful classification of 51.4% of the patients. CONCLUSION: The ADAM and MMAS questionnaires showed adequate sensitivity in diagnosing male patients with low levels of free testosterone. However, because of the lack of specificity, these tools cannot replace calculated free testosterone assessments in men aged 40 years and above.