Relationship between Euthyroidism and Muscle Mass and Strength: A Systematic Review.

Thyroid hormones play a crucial role in skeletal muscle development, suggesting that thyroid function may influence muscle mass and muscle strength, which are both fundamental health-related indicators of several age-related consequences. However, whether there is a relationship between thyroid hormones, muscle mass, and muscle strength in individuals without thyroid dysfunctions is still unknown. Therefore, this systematic review aims to investigate whether thyroid hormones are related to muscle mass and strength parameters in euthyroid individuals. Three databases were searched (PubMed, Scopus, Web of Science) up to February 14, 2022, for peer-reviewed papers published in English. The search results were conducted independently by two different reviewers. The review included 13 studies with a total of 241,044 participants. All studies were observational: twelve studies measured thyroid stimulating hormone, ten and thirteen studies measured free triiodothyronine and free thyroxine, four studies analyzed the thyroid hormone ratio. The assessment methods for muscle mass were computed tomography, dual-energy X-ray absorptiometry and bioimpedance analysis, whereas hand dynamometer for muscle strength. Low levels within the normal range of free triiodothyronine, high levels within the normal range of free thyroxine, and lower thyroid hormone ratio may contribute to a reduced muscle function, which seems more evident in older males.

Clinical Concerns on Sex Steroids Variability in Cisgender and Transgender Women Athletes.

In the female athletic community, there are several endogenous and exogenous variables that influence the status of the hypothalamus-pituitary-ovarian axis and serum sex steroid hormones concentrations (e. g., 17ß-estradiol, progesterone, androgens) and their effects. Moreover, female athletes with different sex chromosome abnormalities exist (e. g., 46XX, 46XY, and mosaicism). Due to the high variability of sex steroid hormones serum concentrations and responsiveness, female athletes may have different intra- and inter-individual biological and functional characteristics, health conditions, and sports-related health risks that can influence sports performance and eligibility. Consequently, biological, functional, and/or sex steroid differences may exist in the same and in between 46XX female athletes (e. g., ovarian rhythms, treated or untreated hypogonadism and hyperandrogenism), between 46XX and 46XY female athletes (e. g., treated or untreated hyperandrogenism/disorders of sexual differentiation), and between transgender women and eugonadal cisgender athletes. From a healthcare perspective, dedicated physicians need awareness, knowledge, and an understanding of sex steroid hormones' variability and related health concerns in female athletes to support physiologically healthy, safe, fair, and inclusive sports participation. In this narrative overview, we focus on the main clinical relationships between hypothalamus-pituitary-ovarian axis function, endogenous sex steroids and health status, health risks, and sports performance in the heterogeneous female athletic community.

Sex-Chromosome-Related Dimorphism in Steroidogenic Enzymes and Androgen Receptor in Response to Testosterone Treatment: An In Vitro Study on Human Primary Skeletal Muscle Cells.

Gender-related methodology in biomedical sciences receives considerable attention, with numerous studies highlighting biological differences between cisgender males and females. These differences influence the clinical symptoms of various diseases and impact therapeutic approaches. In this in vitro study, we investigate the potential role of sex-chromosome-related dimorphism on steroidogenic enzymes, androgen receptor (AR) expression, and cellular translocation in primary human skeletal muscle cells before and after exposure to testosterone. We analyzed 46XY and 46XX cells for 17ß-hydroxysteroid dehydrogenase (17ß-HSD), 5α-reductase (5α-R2), aromatase (Cyp-19), and AR gene expression. We also compared AR expression and intracellular translocation after increasing exposure to testosterone. At baseline, we observed higher mRNA expression for 5α-R2 and AR in 46XY cells and higher Cyp-19 mRNA expression in 46XX cells. Following testosterone exposure, we observed an increase in AR expression and translocation in 46XX cells, even at the lowest dose of 0.5 nM, while significant changes in 46XY cells were observed only from 10 nM. Our in vitro results demonstrate that the diverse sex chromosome assets reflect important differences in muscle steroidogenesis. They support the concept that chromosomal disparities between males and females, even in vitro, lead to pivotal variations in cellular physiology and response. This understanding represents a crucial starting point in gender medicine, ensuring a precise approach in clinical practice, sports, and exercise settings and facilitating the translation of in vitro data to in vivo applicability.

Tadalafil and Steroid Hormones Interactions in Adipose, Bone and Prostate Tissues: Focus on Translational Perspectives.

Tadalafil is a selective phosphodiesterase type-5 (PDE5) inhibitor that is approved for the treatment of men with erectile dysfunction (ED) and/or benign prostate hyperplasia (BPH) -associated symptoms. Besides its classical actions on PDE5 within the genitourinary tract, where the specific enzyme expression is maximal, it may exert different systemic effects. This is mainly due to the pleiotropic distribution of PDE5 enzyme throughout the human (and animal) body, where it can exert protective effects in different clinical conditions. Recently, it has been demonstrated that tadalafil may display novel actions on androgen receptor (AR) expression and activity and cytochrome P19a1 (Cyp19a1) and estrogen receptor ß (ERß) expression in different in vitro systems, such as adipose, bone and prostate cancer cells, where it can act as a selective modulator of steroid hormone production. This may determine novel potential mechanism(s) of control in pathophysiologic pathways. In this review, we summarize basic research and translational results applicable to the use of tadalafil in the treatment of obesity, bone loss and prostate cancer.

Hydrogen Peroxide Stimulates Dihydrotestosterone Release in C2C12 Myotubes: A New Perspective for Exercise-Related Muscle Steroidogenesis?

Skeletal muscle is a tissue that has recently been recognized for its ability to produce androgens under physiological conditions. The steroidogenesis process is known to be negatively influenced by reactive oxygen species (ROS) in reproductive Leydig and ovary cells, while their effect on muscle steroidogenesis is still an unexplored field. Muscle cells are continuously exposed to ROS, resulting from both their metabolic activity and the surrounding environment. Interestingly, the regulation of signaling pathways, induced by mild ROS levels, plays an important role in muscle fiber adaptation to exercise, in a process that also elicits a significant modulation in the hormonal response. The aim of the present study was to investigate whether ROS could influence steroidogenesis in skeletal muscle cells by evaluating the release of testosterone (T) and dihydrotestosterone (DHT), as well as the evaluation of the relative expression of the key steroidogenic enzymes 5α-reductase, 3ß-hydroxysteroid dehydrogenase (HSD), 17ß-HSD, and aromatase. C2C12 mouse myotubes were exposed to a non-cytotoxic concentration of hydrogen peroxide (H2O2), a condition intended to reproduce, in vitro, one of the main stimuli linked to the process of homeostasis and adaptation induced by exercise in skeletal muscle. Moreover, the influence of tadalafil (TAD), a phosphodiesterase 5 inhibitor (PDE5i) originally used to treat erectile dysfunction but often misused among athletes as a "performance-enhancing" drug, was evaluated in a single treatment or in combination with H2O2. Our data showed that a mild hydrogen peroxide exposure induced the release of DHT, but not T, and modulated the expression of the enzymes involved in steroidogenesis, while TAD treatment significantly reduced the H2O2-induced DHT release. This study adds a new piece of information about the adaptive skeletal muscle cell response to an oxidative environment, revealing that hydrogen peroxide plays an important role in activating muscle steroidogenesis.

The Prostacyclin Analogue Iloprost Modulates CXCL10 in Systemic Sclerosis.

The prostacyclin analogue iloprost is used to treat vascular alterations and digital ulcers, the early derangements manifesting in systemic sclerosis (SSc), an autoimmune disease leading to skin and organ fibrosis. Bioindicator(s) of SSc onset and progress are still lacking and the therapeutic approach remains a challenge. The T helper 1 (Th1) chemokine interferon (IFN)γ-induced protein 10 (IP-10/CXCL10) associates with disease progression and worse prognosis. Endothelial cells and fibroblasts, under Th1-dominance, release CXCL10, further enhancing SSc's detrimental status. We analyzed the effect of iloprost on CXCL10 in endothelial cells, dermal fibroblasts, and in the serum of SSc patients. Human endothelial cells and dermal fibroblasts activated with IFNγ/Tumor Necrosis Factor (TNF)α, with/without iloprost, were investigated for CXCL10 secretion/expression and for intracellular signaling cascade underlying chemokine release (Signal Transducer and Activator of Transcription 1, STAT1; Nuclear Factor kappa-light-chain-enhancer of activated B cells, NF-kB; c-Jun NH2-terminal kinase, JNK: Phosphatidyl-Inositol 3-kinase (PI3K)/protein kinase B, AKT; Extracellular signal-Regulated Kinase 1/2, ERK1/2). CXCL10 was quantified in sera from 25 patients taking iloprost, satisfying the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 classification criteria for SSc, and in sera from 20 SSc sex/age-matched subjects without therapy, previously collected. In human endothelial cells and fibroblasts, iloprost targeted CXCL10, almost preventing IFNγ/TNFα-dependent cascade activation in endothelial cells. In SSc subjects taking iloprost, serum CXCL10 was lower. These in vitro and in vivo data suggest a potential role of iloprost to limit CXCL10 at local vascular/dermal and systemic levels in SSc and warrant further translational research aimed to ameliorate SSc understanding/management.

Effects of exercise before and/or after a mixed lunch on postprandial metabolic responses in healthy male individuals.

PURPOSE: Exercise plays an important role in preventing and treating postprandial dysmetabolism. We investigated the postprandial metabolic responses to a standard lunch when a session of aerobic exercise is performed in the early postprandial phase or divided between the pre- and postprandial period. METHODS: Nine healthy volunteers consumed a standardised mixed lunch and rested for the following 3 h (Con) or performed 40 min of cycling at 65% V̇O2max after lunch (CPPEx), or two 20-min sessions, one before (SplitEx1) and the other after lunch (SplitEx2), at the same intensity. RESULTS: At 1-h post-lunch, a significant reduction (P < 0.001) in glycaemia was observed for CPPEx (- 25 ± 10%) and SplitEx (- 34 ± 7%) compared to Con. Yet, a post-exercise rebound lessened the exercise effect on the glycaemic area under the curve (AUC) at 2 and 3 h. At 1 h, a significant reduction (P < 0.009) in plasma insulin (SplitEx - 53 ± 31%; CCPEx - 48 ± 20%) and C-peptide (SplitEx - 57 ± 20%; CCPEx - 47 ± 24%) was observed compared to Con. Glucose-dependent insulinotropic polypeptide (GIP) increased after the meal, without differences between conditions. Compared with SplitEx1, cortisol response was attenuated during SplitEx2 and CPPEx. At 3 hours, triglyceride AUC was significantly higher (P = 0.039) in SplitEx compared to Con (+ 19 ± 8%). CONCLUSION: Forty minutes of postprandial exercise or 20 min of pre- and postprandial exercise are both effective at attenuating the glycaemic and insulinaemic response to a mixed lunch, while a higher lipaemia was found in the pre- and postprandrial exercise condition.

Sildenafil Reduces Expression and Release of IL-6 and IL-8 Induced by Reactive Oxygen Species in Systemic Sclerosis Fibroblasts.

Oxidative stress linked to vascular damage plays an important role in the pathogenesis of systemic sclerosis (SSc). Indeed, vascular damage at nailfold capillaroscopy in patients with Raynaud's Phenomenon (RP) is a major risk factor for the development of SSc together with the presence of specific autoantiobodies. Here, we investigated the effects of the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil, currently used in the management of RP, in modulating the proinflammatory response of dermal fibroblasts to oxidative stress in vitro. Human fibroblasts isolated from SSc patients and healthy controls were exposed to exogenous reactive oxygen species (ROS) (100 µM H2O2), in the presence or absence of sildenafil (1 µM). Treatment with sildenafil significantly reduced dermal fibroblast gene expression and cellular release of IL-6, known to play a central role in the pathogenesis of tissue damage in SSc and IL-8, directly induced by ROS. This reduction was associated with suppression of STAT3-, ERK-, NF-κB-, and PKB/AKT-dependent pathways. Our findings support the notion that the employment of PDE5i in the management of RP may be explored for its efficacy in modulating the oxidative stress-induced proinflammatory activation of dermal fibroblasts in vivo and may ultimately aid in the prevention of tissue damage caused by SSc.

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.

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.

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.

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.

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.

The impact of physical activity on promoter-specific methylation of genes involved in the redox-status and disease progression: A longitudinal study on post-surgery female breast cancer patients undergoing medical treatment.

Most anticancer treatments act on oxidative-stress pathways by producing reactive oxygen species (ROS) to kill cancer cells, commonly resulting in consequential drug-induced systemic cytotoxicity. Physical activity (PA) has arisen as an integrative cancer therapy, having positive health effects, including in redox-homeostasis. Here, we investigated the impact of an online supervised PA program on promoter-specific DNA methylation, and corresponding gene expression/activity, in 3 antioxidants- (SOD1, SOD2, and CAT) and 3 breast cancer (BC)-related genes (BRCA1, L3MBTL1 and RASSF1A) in a population-based sample of women diagnosed with primary BC, undergoing medical treatment. We further examined mechanisms involved in methylating and demethylating pathways, predicted biological pathways and interactions of exercise-modulated molecules, and the functional relevance of modulated antioxidant markers on parameters related to aerobic capacity/endurance, physical fatigue and quality of life (QoL). PA maintained levels of SOD activity in blood plasma, and at the cellular level significantly increased SOD2 mRNA (≈+77 %), contrary to their depletion due to medical treatment. This change was inversely correlated with DNA methylation in SOD2 promoter (≈-20 %). Similarly, we found a significant effect of PA only on L3MBTL1 promoter methylation (≈-25 %), which was inversely correlated with its mRNA (≈+43 %). Finally, PA increased TET1 mRNA levels (≈+15 %) and decreased expression of DNMT3B mRNA (≈-28 %). Our results suggest that PA-modulated DNA methylation affects several signalling pathways/biological activities involved in the cellular oxidative stress response, chromatin organization/regulation, antioxidant activity and DNA/protein binding. These changes may positively impact clinical outcomes and improve the response to cancer treatment in post-surgery BC patients.

Effects of tadalafil on skeletal muscle tissue: exploring interactions and novel mechanisms of action.

Beside its mechanical roles in controlling posture and locomotion, skeletal muscle system, the largest insulin and steroid hormones target tissue, plays a key role in influencing thermoregulation, secondary sexual characteristics, hormones metabolism, and glucose uptake and storage, as well as energetic metabolism. Indeed, in addition to insulin, several hormones influence the skeletal muscle metabolism/function and/or are influenced by skeletal muscles activity (i.e., physical exercise). Particularly, steroid hormones play a key role in modulating many biological processes in muscles, essential for overall muscle's function and homeostasis, both at rest and during all physical activities (i.e., physical exercise, muscular work). Phosphodiesterase type 5 (PDE5) is the enzyme engaged to hydrolyze cyclic guanosine monophosphate (cGMP) in inactive 5'-GMP form. Therefore, through the inhibition of this enzyme, the intracellular level of cGMP increases, and the cGMP-related cellular responses are prolonged. Different drugs inhibiting PDE5 (PDE5i) exist, and the commercially available PDE5i are sildenafil, vardenafil, tadalafil, and avanafil. The PDE5i tadalafil may influence cellular physiology and endocrine-metabolic pathways in skeletal muscles and exerts its functions both by activating the cell signaling linked to the insulin-related metabolic pathways and modulating the endocrine responses, protein catabolism and hormone-related anabolism/catabolism during and after physical exercise-related stress. Based on recent in-vivo and in-vitro findings, in this narrative review the aim was to summarize the available evidence describing the interactions between the PDE5i tadalafil and steroid hormones in skeletal muscle tissue and physical exercise adaptation, focusing our interest on their possible synergistic or competitive action(s) on muscle metabolism and function.

Steady-state redox status in circulating extracellular vesicles: A proof-of-principle study on the role of fitness level and short-term aerobic training in healthy young males.

Considering the role of redox homeostasis in exercise-induced signaling and adaptation, this study focuses on the exercise training-related intercellular communication of redox status mediated by circulating extracellular vesicles (EVs). 19 healthy young males were divided into trained (TG, 7) and untrained (UG, 12) subjects based on their VO2MAX. The UG subjects were further randomly distributed in experimental (UGEX, N = 7) and control (UGCTRL, N = 5) groups. The steady state of plasma EVs in TG and UGEX have been characterized for total number and size, as well as cargo redox status (antioxidants, transcription factors, HSPs) before, 3 and 24 h after a single bout of aerobic exercise (30', 70% HRM). Plasma EVs from UGEX and UGCTRL have been further characterized after 24 h from the last session of a 5-day consecutive aerobic training or no training, respectively. No differences were detected in the EVs' size and distribution at baseline in TG and UGEX (p>0.05), while the EVs cargo of UGEX showed a significantly higher concentration of protein carbonyl, Catalase, SOD2, and HSF1 compared to TG (p<0.05). 5 days of consecutive aerobic training in UGEX did not determine major changes in the steady-state number and size of EVs. The post-training levels of protein carbonyl, HSF1, Catalase, and SOD2 in EVs cargo of UGEX resulted significantly lower compared with UGEX before training and UGCTRL, resembling the steady-state levels in circulating EVs of TG subjects. Altogether, these preliminary data indicate that individual aerobic capacity influences the redox status of circulating EVs, and that short-term aerobic training impacts the steady-state redox status of EVs. Taking this pilot study as a paradigm for physio-pathological stimuli impacting redox homeostasis, our results offer new insights into the utilization of circulating EVs as biomarkers of exercise efficacy and of early impairment of oxidative-stress related diseases.

Positive effects of dietary supplementation with nutraceuticals on male subclinical hypogonadism: a pilot study.

BACKGROUND: Lifestyle modifications (i.e., physical activity [PA] and lower dietary intake) often are not sufficient to improve testosterone (TE) levels and promote weight loss in men with metabolic hypogonadism. The aim of the study was to investigate the effects of a nutraceutical formulation containing myoinositol, alpha lipoic acid, folic acid and SelectSIEVE® as add-on treatment to lifestyle modifications in improving obesity-related subclinical hypogonadism. METHODS: Body composition, insulin resistance, testicular and erectile function were investigated in 15 males (age=39.5±14.5 years; Body Mass Index [BMI]=30.2±3.8 kg/m2, with subclinical hypogonadism (TE levels <14 and normal luteinizing hormone [LH]). After a run-in three months unsupervised PA period (T1), the nutraceutical supplement was administered two-times per day for three additional months (T2). RESULTS: BMI, the percentage fat mass, insulinemia and Homeostasis Model Assessment Index (P<0.01) along with glycemia (P<0.05) were significantly reduced at T2 compared to T1, respectively; fat free mass (FFM) was significantly higher at T2 compared to T1 (P<0.01). Also, TE, LH and 5-item international index of erectile function score were significantly increased at T2 compared to T1 (P<0.01), respectively. CONCLUSIONS: The combination of unsupervised PA and nutraceutical supplement improves body composition, insulin sensitivity and TE production in overweight-obese men with metabolic hypogonadism. Further controlled studies in the long-term are warranted to elucidate potential changes in fertility.

Plasma-derived extracellular vesicles released after endurance exercise exert cardioprotective activity through the activation of antioxidant pathways.

Cardiovascular diseases (CVD) can cause various conditions, including an increase in reactive oxygen species (ROS) levels that can decrease nitric oxide (NO) availability and promote vasoconstriction, leading to arterial hypertension. Physical exercise (PE) has been found to be protective against CVD by helping to maintain redox homeostasis through a decrease in ROS levels, achieved by increased expression of antioxidant enzymes (AOEs) and modulation of heat shock proteins (HSPs). Extracellular vesicles (EVs) circulating in the body are a major source of regulatory signals, including proteins and nucleic acids. Interestingly, the cardioprotective role of EVs released after PE has not been fully described. The aim of this study was to investigate the role of circulating EVs, obtained through Size Exclusion Chromatography (SEC) of plasma samples from healthy young males (age: 26.95 ± 3.07; estimated maximum oxygen consumption rate (VO2max): 51.22 ± 4.85 (mL/kg/min)) at basal level (Pre_EVs) and immediately after a single bout of endurance exercise (30' treadmill, 70% heart rate (HR) -Post_EVs). Gene ontology (GO) analysis of proteomic data from isolated EVs, revealed enrichment in proteins endowed with catalytic activity in Post_EVs, compare to Pre_EVs, with MAP2K1 being the most significantly upregulated protein. Enzymatic assays on EVs derived from Pre and Post samples showed increment in Glutathione Reductase (GR) and Catalase (CAT) activity in Post_EVs. At functional level, Post_EVs, but not Pre_EVs, enhanced the activity of antioxidant enzymes (AOEs) and reduced oxidative damage accumulation in treated human iPS-derived cardiomyocytes (hCM) at basal level and under stress conditions (Hydrogen Peroxide (H2O2) treatment), resulting in a global cardioprotective effect. In conclusion, our data demonstrated, for the first time, that a single 30-min endurance exercise is able to alter the cargo of circulating EVs, resulting in cardioprotective effect through antioxidant activity.

Online Home-Based Physical Activity Counteracts Changes of Redox-Status Biomarkers and Fitness Profiles during Treatment Programs in Postsurgery Female Breast Cancer Patients.

Breast cancer (BC) is one of the most commonly diagnosed types of cancer in women. Oxidative stress may contribute to cancer etiology through several mechanisms. A large body of evidence indicates that physical activity (PA) has positive effects on different aspects of BC evolution, including mitigation of negative effects induced by medical treatment. With the aim to verify the capacity of PA to counteract negative effects of BC treatment on systemic redox homeostasis in postsurgery female BC patients, we have examined the modulation of circulating levels of oxidative stress and inflammation markers. Moreover, we evaluated the impacts on physical fitness and mental well-being by measuring functional parameters, body mass index, body composition, health-related quality of life (QoL), and fatigue. Our investigation revealed that PA was effective in maintaining plasma levels of superoxide dismutase (SOD) activity and tGSH, as well as peripheral blood mononuclear cells' (PBMCs) mRNA levels of SOD1 and heat-shock protein 27. Moreover, we found a significant decrease in plasma interleukin-6 (≈0.57 ± 0.23-fold change, p < 0.05) and increases in both interleukin-10 (≈1.15 ± 0.35-fold change, p < 0.05) and PBMCs' mRNA level of SOD2 (≈1.87 ± 0.36-fold change, p < 0.05). Finally, PA improves functional parameters (6 min walking test, ≈+6.50%, p < 0.01; Borg, ≈-58.18%, p < 0.01; sit-and-reach, ≈+250.00%, p < 0.01; scratch right, ≈-24.12%, and left, ≈-18.81%, p < 0.01) and body composition (free fat mass, ≈+2.80%, p < 0.05; fat mass, ≈-6.93%, p < 0.05) as well as the QoL (physical function, ≈+5.78%, p < 0.05) and fatigue (cognitive fatigue, ≈-60%, p < 0.05) parameters. These results suggest that a specific PA program not only is effective in improving functional and anthropometric parameters but may also activate cellular responses through a multitude of actions in postsurgery BC patients undergoing adjuvant therapy. These may include modulation of gene expression and protein activity and impacting several signaling pathways/biological activities involved in tumor-cell growth; metastasis; and inflammation, as well as moderating distress symptoms known to negatively affect QoL.

The phosphodiesterases type 5 inhibitor tadalafil reduces the activation of the hypothalamus-pituitary-adrenal axis in men during cycle ergometric exercise.

Phosphodiesterase type 5 inhibitors may influence human physiology, health, and performance by also modulating endocrine pathways. We evaluated the effects of a 2-day tadalafil administration on adenohypophyseal and adrenal hormone adaptation to exercise in humans. Fourteen healthy males were included in a double-blind crossover trial. Each volunteer randomly received two tablets of placebo or tadalafil (20 mg/day with a 36-h interval) before a maximal exercise was performed. After a 2-wk washout, the volunteers were crossed over. Blood samples were collected at -30 and -15 min and immediately before exercise, immediately after, and during recovery (+15, +30, +60, and +90 min) for adrenocorticotropin (ACTH), ß-endorphin, growth hormone (GH), prolactin, cortisol (C), corticosterone, dehydroepiandrosterone-sulfate (DHEAS), and cortisol binding globulin (CBG) assays. C-to-CBG (free cortisol index, FCI) and DHEAS-to-C ratios were calculated. Exercise intensity, perceived exertion rate, O2 consumption, and CO2 and blood lactate concentration were evaluated. ACTH, GH, C, corticosterone, and CBG absolute concentrations and/or areas under the curve (AUC) increased after exercise after both placebo and tadalafil. Exercise increased DHEAS only after placebo. Compared with placebo, tadalafil administration reduced the ACTH, C, corticosterone, and FCI responses to exercise and was associated with higher ß-endorphin AUC and DHEAS-to-C ratio during recovery, without influencing cardiorespiratory and performance parameters. Tadalafil reduced the activation of the hypothalamus-pituitary-adrenal axis during exercise by probably influencing the brain's nitric oxide- and cGMP-mediated pathways. Further studies are necessary to confirm our results and to identify the involved mechanisms, possible health risks, and potential clinical uses.