Effects of transdermal administration of testosterone gel on the urinary steroid profile in hypogonadal men: Implications in antidoping analysis.

Testosterone is one of the most abused pseudo-endogenous anabolic steroids in sport doping. The current method adopted to detect the abuse of testosterone and other pseudo-endogenous steroids (endogenous steroids when administered exogenously) is first based on the longitudinal monitoring of several urinary biomarkers, which constitute the so called "steroidal module" of the Athlete Biological Passport (ABP): atypical samples undergo a confirmation analysis based on the measurement of the 13C/12C isotopic ratio of selected target compounds, to distinguish their endogenous or exogenous origin. At the same time, testosterone administration can be allowed in athletes diagnosed with hypogonadism, provided they are granted a therapeutic use exemption by the relevant medical authority. In this pilot study we have investigated whether the approach based on the preliminary determination of the urinary steroid profile, in the format considered in the steroidal module of the ABP, also integrated with the inclusion of the sulfo-conjugates and of additional target steroids, can retain its validity also in the case of hypogonadal athletes. We have studied the effects of a single low dose (40 mg) of testosterone gel (T-gel) on the urinary concentration of the markers of steroidal module of the ABP, as well as on some additional steroid markers. The study was based on the analysis of urinary samples from 19 non-hospitalized hypogonadal men, 10 of them with late-onset hypogonadism (LOH), collected before, after 4 h and after 24 h the transdermal self-administration of 40 mg of T-gel. None of the patient had any co-morbidities possibly affecting the urinary excretion of the steroidal markers. The steroidal markers were quantified by gas chromatography coupled to tandem mass spectrometry (GC-MS/MS) after the enzymatic hydrolysis of the respective glucuro-conjugates and the chemical hydrolysis of the respective sulfo-conjugates. Targeted GC-MS/MS analysis was carried out operating in electron impact (EI) ionization mode, with acquisition in multiple reaction monitoring (MRM) mode. Our preliminary results show that, as expected, the treatment with T-gel leads, in all hypogonadal men, to an increase of the urinary concentration of the glucuro-conjugate metabolites of testosterone and its main metabolites, with special relevance to those with 5α-reduction. Furthermore, samples collected from non-LOH hypogonadal men showed an increase also in the levels of epitestosterone glucuronide, testosterone sulfate and epitestosterone sulfate. Apart from their biochemical and pharmacological relevance, these outcomes could be leveraged to refine the analytical strategy currently followed in the antidoping field for the analysis of the urinary steroidal markers, with potential implications also in other forensic and/or clinical investigations.

Endocrine Disrupting Chemicals: Effects on Endocrine Glands.

In recent years, endocrine disrupting chemicals have gained interest in human physiopathology and more and more studies aimed to explain how these chemicals compounds affect endocrine system. In human populations, the majority of the studies point toward an association between exposure to endocrine disrupting chemicals and the disorders affecting endocrine axis. A great number of endocrine disrupting chemicals seem to be able to interfere with the physiology of hypothalamus-pituitary-gonadal axis; however, every endocrine axis may be a target for each EDCs and their action is not limited to a single axis or organ. Several compounds may also have a negative impact on energy metabolic homeostasis altering adipose tissue and promoting obesity, metabolic syndrome, and diabetes. Different mechanism have been proposed to explain these associations but their complexity together with the degree of occupational or environmental exposure, the low standardization of the studies, and the presence of confounding factors have prevented to establish causal relationship between the endocrine disorders and exposure to specific toxicants so far. This manuscript aims to review the state of art of scientific literature regarding the effects of endocrine-disrupting chemicals (EDCs) on endocrine system.

Physical exercise, nutrition and hormones: three pillars to fight sarcopenia.

BACKGROUND: Sarcopenia is a pathophysiological condition diffused in elderly people; it represents a social issue due to the longer life expectancy and the growing aging population. It affects negatively quality of life and it represents a risk factor for other pathologies, such as diabetes, cardiovascular disease, and obesity. No silver bullet exists to hinder sarcopenia, but it may be counteracted by physical exercise, nutrition, and a proper endocrine milieu. Indeed, we aim to analyze the scientific literature to give to clinician effective advices to counteract sarcopenia. Main text: Physical exercise, proper nutrition, optimized hormonal homeostasis represent the three pillars to fight sarcopenia. Physical exercise represents the most effective remedy to face sarcopenia, in particular if it is combined with a proper diet and with an adequate endocrine milieu. Consistency in training, adequate daily protein intake and eugonadism seems to be the keys to fight sarcopenia. The combination of these three pillars might act synergistically. CONCLUSIONS: Optimization of these factors may increase their efficiency; however, scientific data may be sometimes confusing so far. Therefore, we aim to give practical advices to clinician to identify and to highlight the most important aspects in each of these three factors that should be addressed.

Effects of Ketone Bodies on Endurance Exercise.

Priorities for every athlete include improving endurance performance, optimizing training, nutrition, and recovery. Nutritional strategies are crucial to support athletes to perform at the highest level, and considering that muscular and hepatic glycogen stores are limited, alternative strategies to maximize fat metabolism have been suggested. A ketogenic diet has been proposed as a possible method of providing metabolic fuel during prolonged periods of exercise. However, clinical trials and empirical experience have produced contrasting results regarding the ergogenic value of a ketogenic diet. For this reason, using ketone esters and/or salts have been proposed to obtain nutritional ketosis without limiting carbohydrate intake. Exogenous ketones should not only represent an alternative metabolic fuel source, sparing carbohydrates, but they also may increase postexercise glycogen replenishment, decrease proteolysis, and act as metabolic modulators and signaling metabolites. While there are some encouraging results showing an increase in endurance performance, contrasting evidence regarding the efficacy of exogenous ketones for endurance performance is present and further studies should be performed to make a definitive statement.

Sport, doping and male fertility.

It is universally accepted that lifestyle interventions are the first step towards a good overall, reproductive and sexual health. Cessation of unhealthy habits, such as tobacco, alcohol and drug use, poor nutrition and sedentary behavior, is suggested in order to preserve/improve fertility in humans. However, the possible risks of physical exercise per se or sports on male fertility are less known. Being "fit" does not only improve the sense of well-being, but also has beneficial effects on general health: in fact physical exercise is by all means a low-cost, high-efficacy method for preventing or treating several conditions, ranging from purely physical (diabetes and obesity) to psychological (depression and anxiety), highly influencing male reproduction. If male sexual and reproductive health could be positively affected by a proper physical activity, inadequate bouts of strength - both excessive intensity and duration of exercise training - are more likely to have detrimental effects. In addition, the illicit use of prohibited drugs (i.e. doping) has reached pandemic proportions, and their actions, unfortunately very often underestimated by both amateur and professional athletes, are known to disrupt at different levels and throughout various mechanisms the male hypothalamic-pituitary-gonadal axis, resulting in hypogonadism and infertility.

Serum Homocysteine Levels in Men with and without Erectile Dysfunction: A Systematic Review and Meta-Analysis.

OBJECTIVES: Elevated levels of serum homocysteine (Hcy) have been associated with cardiovascular diseases and endothelial dysfunction, conditions closely associated with erectile dysfunction (ED). This meta-analysis was aimed to assess serum Hcy levels in subjects with ED compared to controls in order to clarify the role of Hcy in the pathogenesis of ED. METHODS: Medline, Embase, and the Cochrane Library were searched for publications investigating the possible association between ED and Hcy. Results were restricted by language, but no time restriction was applied. Standardized mean difference (SMD) was obtained by random effect models. RESULTS: A total of 9 studies were included in the analysis with a total of 1320 subjects (489 subjects with ED; 831 subjects without ED). Pooled estimate was in favor of increased Hcy in subjects with ED with a SMD of 1.00, 95% CI 0.65-1.35, p < 0.0001. Subgroup analysis based on prevalence of diabetes showed significantly higher SMD in subjects without diabetes (1.34 (95% CI 1.08-1.60)) compared to subjects with diabetes (0.68 (95% CI 0.39-0.97), p < 0.0025 versus subgroup w/o diabetes). CONCLUSIONS: Results from our meta-analysis suggest that increased levels of serum Hcy are more often observed in subjects with ED; however, increase in Hcy is less evident in diabetic compared to nondiabetic subjects. This study is registered with Prospero registration number CRD42018087558.

Folate: a possible role in erectile dysfunction?

A growing body of evidence suggests a role for homocysteine (Hcys) and folate (FA) in erectile function (EF): Hcys appears to impair EF affecting endothelium via several mechanism whereas the role of FA remains to be elucidated, besides decreasing Hcys. To assess correlation between erectile dysfunction (ED) and serum levels of FA, Hcys, and B12, we enrolled 31 patients affected by ED (Group A; age 52.83 ± 11.89 years) and 31 healthy adults (Group B; age 49.14 ± 13.63 years). Fasting blood samples were taken for each subject. ED was assessed by the International Index of Erectile Function-5 (IIEF-5). IIEF-5 mean score was significantly lower in Group A than in Group B (10.71 ± 4.24 versus 23.32 ± 1.33, p < .001). Compared to Group B, Group A also showed significantly lower serum FA levels (5.11 ± 1.79 versus 7.9 ± 3.55 ng/ml, p < .001) and significantly higher serum Hcys levels (13.61 ± 3.55 versus 9.17 ± 2.32 µmol/L, p < .001). No significant correlation was observed between Hcys and FA both groups. Our results showed a significant association among ED, FA deficiency and hyperomocisteinemia. Lack of correlation between FA and Hcys suggests that FA deficit may directly impair EF.

Effects of erythropoietin abuse on exercise performance.

The present review provides a comprehensive overview on the erythropoietic and non-erythropoietic effects of rHuEpo on human sport performance, paying attention to quantifying numerically how rHuEpo affects exercise performance and describing physiological changes regarding the most important exercise variables. Much attention has been paid to treatment schedules, in particular, to assess the effects of microdoses of rHuEpo and the prolonged effects on sport performance following withdrawal. Moreover, the review takes into account non-erythropoietic ergogenic effects of rHuEpo, including cognitive benefits of rHuEpo. A significant increase in both Vo2max and maximal cycling power was evidenced in studies taken into account for this review. rHuEpo, administered at clinical dosage, may have significant effects on haematological values, maximal and submaximal physiological variables, whereas few reports show positive effects on exercise perfomance. However, the influence of micro-dose rHuEpo on endurance performance in athletes is still unclear and further studies are warranted.

Phosphodiesterase Type 5 Inhibitors, Sport and Doping.

Phosphodiesterase type 5 inhibitors (PDE5i) (e.g., sildenafil, tadalafil, vardenafil, and avanafil) are drugs commonly used to treat erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia. PDE5i are not prohibited by the World Anti-Doping Agency (WADA) but are alleged to be frequently misused by healthy athletes to improve sporting performance. In vitro and in vivo studies have reported various effects of PDE5i on cardiovascular, muscular, metabolic, and neuroendocrine systems and the potential, therefore, to enhance performance of healthy athletes during training and competition. This suggests well-controlled research studies to examine the ergogenic effects of PDE5i on performance during activities that simulate real sporting situations are warranted to determine if PDE5i should be included on the prohibited WADA list. In the meantime, there is concern that some otherwise healthy athletes will continue to misuse PDE5i to gain an unfair competitive advantage over their competitors.

Pituitary hyperplasia mimicking macroadenoma associated with primary hypothyroidism in a patient with selective L-thyroxine malabsorption.

We present the case of a 29-year-old woman who developed a severe hypothyroidism induced by a thyroxine malabsorption and a secondary pituitary hyperplasia. We performed thyroxine absorption tests to diagnose the malabsorption and to evaluate the best therapeutic intervention. Once assessed a correct therapy lowering TSH, we observed the regression of pituitary mass confirming our diagnosis of secondary pituitary hyperplasia. We suggest to evaluate any possible reason for thyroxine malabsorption and to consider the hypothesis of pituitary hyperplasia in the presence of pituitary mass together with overt hypothyroidism.

Relationship Between Use of Videogames and Sexual Health in Adult Males.

BACKGROUND: Videogame use is increasingly prevalent in people of all ages, and despite the wide amount of scientific evidence proving a role for electronic entertainment in human health, there is no evidence about the relation between use of videogames and sexual health. AIM: To investigate the association between use of videogames and male sexual health. METHODS: We administered the two validated questionnaires, the Premature Ejaculation Diagnostic Tool (PEDT) and the International Index of Erectile Function (IIEF-15), to men 18 to 50 years old recruited through social networks and specific websites. In addition to the questionnaires, volunteers were asked to provide information on their gaming habit and lifestyle. OUTCOMES: An extended version of the IIEF-15 and PEDT, including data about gaming habits and relevant lifestyles. RESULTS: From June 18, 2014 through July 31, 2014, 599 men 18 to 50 years old completed the questionnaires. One hundred ninety-nine men reported no sexual activity during the previous 4 weeks; four records were rejected because of inherent errors. The remaining 396 questionnaires were analyzed, with 287 "gamers" (playing >1 hour/day on average) and 109 "non-gamers" providing all the required information. We found a lower prevalence of premature ejaculation in gamers compared with non-gamers (mean PEDT score = 3.57 ± 3.38 vs 4.52 ± 3.7, P < .05, respectively). Analysis of the IIEF-15 showed no significant differences between gamers and non-gamers in the domains of erectile function, orgasmic function, and overall satisfaction. Median scores for the sexual desire domain were higher for non-gamers (median score [interquartile range] 9 [8-9] vs 9 [8-10], respectively; P = .0227). CLINICAL IMPLICATIONS: These results support the correlation between videogame use and male sexual health. Compared with non-gamers, men playing videogames for more than 1 hour/day were less likely to have premature ejaculation but more likely to have decreased sexual desire. STRENGTHS AND LIMITATIONS: This is the first study aimed to assess male sexual health in gamers. We identified an association between PEDT and IIEF scores and videogame use; however, these findings require validation through interventional studies. Furthermore, volunteers were recruited through social networks, thus increasing the risk of recruitment bias. CONCLUSION: To our knowledge, this is the first observational study investigating the link between electronic entertainment and male sexuality, specifically for ejaculatory response and sexual desire. Sansone A, Sansone M, Proietti M, et al. Relationship Between Use of Videogames and Sexual Health in Adult Males. J Sex Med 2017;14:898-903.

Gynecomastia and hormones.

Gynecomastia-the enlargement of male breast tissue in men-is a common finding, frequently observed in newborns, adolescents, and old men. Physiological gynecomastia, occurring in almost 25 % of cases, is benign and self-limited; on the other hand, several conditions and drugs may induce proliferation of male breast tissue. True gynecomastia is a common feature often related to estrogen excess and/or androgen deficiency as a consequence of different endocrine disorders. Biochemical evaluation should be performed once physiological or iatrogenic gynecomastia has been ruled out. Non-endocrine illnesses, including liver failure and chronic kidney disease, are another cause of gynecomastia which should be considered. Treating the underlying disease or discontinuing medications might resolve gynecomastia, although the psychosocial burden of this condition might require different and careful consideration.

Testosterone Replacement Therapy: The Emperor's New Clothes.

The mean age of the world population has steadily increased in the last decades, as a result of increased life expectancy and reduced birth rate. Global aging has led to a greater worldwide cost for healthcare: hormonal alterations contribute to the pathogenesis of several conditions and might cause a significant reduction in the perceived sense of well-being. Menopause is archetypal of hormonal alterations occurring during aging: in males, sex hormones do not decrease abruptly, yet testosterone levels decrease steadily and continuously during aging, ultimately resulting in late-onset hypogonadism. Treatment of this condition might mitigate most symptoms; however, testosterone replacement therapy (TRT) should be prescribed only in selected patients and it should not be considered as an antiaging treatment. In recent years, different authors have questioned health risks associated with testosterone treatment; while position statements from many scientific societies seem to be reassuring, the Food and Drug Administration has issued a warning in regard to the possible side effects of this therapy. We aim to review recent controversies and discoveries in regard to TRT.

Effects of tadalafil administration on plasma markers of exercise-induced muscle damage, IL6 and antioxidant status capacity.

INTRODUCTION: Physical exercise is associated with enhanced production of reactive oxygen species, which if uncontrolled can result in tissue injury. Phosphodiesterase type 5 inhibitors (PDE5i) exhibit protective effect against oxidative stress, both in animals and healthy/unhealthy humans. However, the effect of a chronic administration of PDE5i, particularly combined with physical exercise, has never been investigated. PURPOSE: The present study was designed to evaluate the effect of the long-acting PDE5i tadalafil on oxidative status and muscle damage after exhaustive exercise in healthy males included in a double-blind crossover trial. HYPOTHESIS: Tadalafil, having a putative antioxidant activity, may reduce oxidative damage after strenuous exercise. METHODS: Each volunteer randomly received two tablets of placebo or tadalafil (20 mg/day) with 36 h of interval before performing exhaustive exercise. After 2 weeks of washout, the volunteers were crossed over. Blood samples were collected immediately before exercise, immediately after, and during recovery (15, 30, 60 min). Plasma total antioxidant status, glutathione homeostasis (GSH/GSSG), malondialdehyde (MDA), protein carbonyls, creatine kinase (CK), lactate dehydrogenase (LDH) and the inflammatory cytokine interleukin 6 were assessed. RESULTS: Tadalafil administration per se affected redox homeostasis (GSH/GSSG -36%; p < 0.05), cellular (CK +75% and LDH +36%; p < 0.05) and oxidative damage (MDA +41% and protein carbonyls +50%; p < 0.05) markers. The exhaustive exercise increased all the above-reported biochemical parameters, with subjects from the tadalafil group showing significantly higher values with respect to the placebo group. CONCLUSIONS: A prolonged exposure to tadalafil decreases antioxidant capacity at resting condition, therefore making subjects more susceptible to the oxidative stress induced by an exhaustive bout of exercise.

Acute effects of physical exercise and phosphodiesterase's type 5 inhibition on serum 11ß-hydroxysteroid dehydrogenases related glucocorticoids metabolites: a pilot study.

Endogenous glucocorticoids (GC) rapidly increase after acute exercise, and the phosphodiesterase's type 5 inhibitor (PDE5i) tadalafil influences this physiological adaptation. No data exist on acute effects of both acute exercise and PDE5i administration on 11ß-hydroxysteroid dehydrogenases (11ß-HSDs)-related GC metabolites. We aimed to investigate the rapid effects of exercise on serum GC metabolites, with and without tadalafil administration. A double blind crossover study was performed in eleven healthy male volunteers. After the volunteers randomly received a short-term administration of placebo or tadalafil (20 mg/die for 2 days), a maximal exercise test to exhaustion on cycle ergometer was performed. Then, after a 2-week washout period, the volunteers were crossed over. Blood samples were collected before starting exercise and at 5 and 30 min of recovery (+5-Rec, +30-Rec). Serum ACTH, corticosterone (Cn), cortisol (F), cortisone (E), tetrahydrocortisol (THF), tetrahydrocortisone (THE), cortols, cortolones and respective ratios were evaluated. Pre-Ex THF was higher after tadalafil. Exercise increased ACTH, Cn, F, E, THE, cortols and cortolones after both placebo and tadalafil, and THF after placebo. The F/E ratio increased at +5-Rec and decreased at +30-Rec after placebo. Compared to placebo, after tadalafil lower ACTH, F and Cn, higher THF/F and THE/E, and not E (at +5-Rec) and F/E modifications were observed. Acute exercise rapidly influences serum GC metabolites concentrations. Tadalafil influences both GC adaptation and 11ß-HSDs activity during acute exercise. Additional researches on the effects of both exercise and PDE5i on tissue-specific 11ß-HSDs activity at rest and during physiological adaptation are warranted.