Paolo Sgrò

Use of carnitine therapy in selected cases of male factor infertility: A double-blind crossover trial

OBJECTIVE To determine the efficacy of L-carnitine therapy in selected cases of male factor infertility. DESIGN Placebo-controlled, double-blind, crossover trial. SETTING University tertiary referral center. PATIENT(S) One hundred infertile patients (ages 20-40 years) with the following baseline sperm selection criteria: concentration, 10-20 x 10(6)/mL; total motility, 10%-30%; forward motility, <15%; atypical forms, <70%; velocity, 10-30 micro/s; linearity, <4. Eighty-six patients completed the study. INTERVENTION(S) Patients underwent L-carnitine therapy 2 g/day or placebo; the study design was 2 months of washout, 2 months of therapy/placebo, 2 months of washout, and 2 months placebo/therapy. MAIN OUTCOME MEASURE(S) Variation in sperm parameters used in the patients selection criteria, in particular, sperm motility. Excluding outliers, a statistically significant improvement in semen quality, greater than after the placebo cycle, was seen after the L-carnitine therapy for sperm concentration and total and forward sperm motility. The increase in forward sperm motility was more significant in those patients with lower initial values, i.e., <5 x 10(6) or <2 x 10(6) of forward motile sperm/ejaculate or sperm/mL. CONCLUSION(S) Based on a controlled study of efficacy, L-carnitine therapy was effective in increasing semen quality, especially in groups with lower baseline levels. However, these results need to be confirmed by larger clinical trials and in vitro studies.

Andrological aspects of physical exercise and sport medicine

Appropriate physical activity is one of the bases of healthy lifestyle. In fact, physical exercise and playing sport may be associated with both improvements and injury to both general and reproductive health. A biologically normal testosterone secretion appears fundamental in males to guarantee both a physiological exercise adaptation and safe sport participation. The reproductive system is highly sensitive to the effects of exercise-related stress and the reproductive hormones may both increase and decrease after different acute or chronic exercises. Exercise and sport participation may positively or negatively influence andrological health status depending on the type, intensity and duration of performed physical activity and on individual health status. In addition, prohibited substances administration (e.g. androgenic–anabolic steroids, and so forth) in competitive and non-competitive athletes represents the main cause of iatrogenic andrological diseases. Preventing and treating andrological problems in active healthy and unhealthy individuals is as important as promoting a correct lifestyle. Physicians need to be educated on the relationships between the male reproductive system and sport participation and on the great role of the pre-participation physical examination in the prevention of andrological diseases.

The Type 5 Phosphodiesterase Inhibitor Tadalafil Influences Salivary Cortisol, Testosterone, and Dehydroepiandrosterone Sulphate Responses to Maximal Exercise in Healthy Men

CONTEXT Physical exercise-related stress activates hypothalamus-pituitary-adrenal (HPA) axis; nitric oxide is one of the mediators of the HPA axis response to stress, and phosphodiesterase type 5 inhibitors influences nitric oxide-linked biological activities. OBJECTIVE The objective of the study was to investigate whether a single oral long half-life phosphodiesterase type 5 inhibitor (tadalafil) administration influences the HPA axis response to exercise-related stress. DESIGN This was a double-blind, cross-over trial. PARTICIPANTS Participants included nine healthy male athletes. INTERVENTIONS All subjects performed a maximal exercise test in normoxia, after which they received a single oral administration of tadalafil or placebo. Then after a 2-wk washout period, they were crossed over and repeated the exercise test. Each subject was his own control. Salivary collections, for steroid evaluations [cortisol, dehydroepiandrosterone sulphate (DHEAS), testosterone] and respective ratio calculation (DHEAS to cortisol, testosterone to cortisol, testosterone to DHEAS), were performed before each exercise (Pre-Ex), immediately after (Post-Ex), and at 30 min during recovery. RESULTS As expected, mean salivary cortisol concentration increased immediately after exercise after both tadalafil and placebo (P = 0.014 and P =0.036 vs. Pre-Ex, respectively); however, the cortisol increase was significantly higher after tadalafil administration (P = 0.034 vs. placebo). Furthermore, an increased salivary testosterone after exercise was observed only after tadalafil administration (P = 0.029 vs. Pre-Ex). No effects of either exercise and/or tadalafil administration on salivary DHEAS concentrations were observed. DHEAS to cortisol and testosterone to cortisol ratios significantly decreased after exercise after tadalafil administration (P = 0.037, and P = 0.02 vs. placebo, respectively). CONCLUSION Tadalafil administration amplified the salivary cortisol and testosterone responses to a maximal exercise-related stress in healthy trained humans.

Is explosive performance influenced by androgen concentrations in young male soccer players

Objective: There is growing interest in the implementation and assessment of strength and conditioning programmes among young children. The purpose of this study was to examine the association between given anthropometric characteristics, pubertal development, salivary androgen hormones and explosive leg power in young soccer players. Methods: 51 (age range 10–14 years) soccer players were investigated. The relations between age, pubertal developmental stages, testicular volume, weight, height, body fat, fat free mass, salivary DHEAS concentrations, salivary testosterone concentrations and lower limb explosive power were evaluated. Results: Standing long jump length was positively correlated (p<0.05) with age (11.7 (SD 1.2) years, r = 0.66), pubertal developmental stages (mode and range: 1 (1–4), r = 0.64), testicular volume (8.8 (5.2) ml, r = 0.58), height (1.50 (0.10) m, r = 0.34), weight (43.7 (9.1) kg, r = 0.34), fat free mass (35.4 (7.2) kg, r = 0.67), salivary DHEAS concentrations (4.4 (1.2) ng/ml, r = 0.38) and negatively correlated with body fat (18.6 (7.0) kg; r = −0.49, p<0.05). There was no significant correlation between salivary testosterone concentrations (0.3 (0.1) ng/ml, r = 0.12) and standing long jump. Conclusions: Results of the present investigation demonstrated that age, pubertal developmental stages, testicular volume, weight, height, fat free mass, and salivary DHEAS concentrations were associated with standing long jump performance. In addition, salivary testosterone concentrations were not related to explosive leg power. Results of the present investigation suggest that the teacher/coach should evaluate long jump performance relative to the subject’s given biological characteristics, and not simply established standards based on chronological age.

Prevalence of Undiagnosed Testosterone Deficiency in Aging Athletes: Does Exercise Training Influence the Symptoms of Male Hypogonadism?

INTRODUCTION Worldwide many aging males practice sports. A high prevalence of late-onset male hypogonadism has been observed in general population. Sport-participation influences the neuroendocrine system and may decrease serum testosterone. AIM This preliminary study was designed to estimate the prevalence and the symptoms of undiagnosed testosterone deficiency in aging athletes. METHODS This observational survey was performed in 183 caucasian male athletes >50 years, in the setting of pre-participation screening. Pituitary-gonadal hormones and symptoms of hypogonadism were investigated. Serum total testosterone (TT), sex hormone binding globulin, luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), free-T4, and thyroid stimulation hormone (TSH) were assayed, and free T, bioactive T, and the LH/TT ratio were calculated. The International Index of Erectile Dysfunction (IIEF-15) and the Center for Epidemiological Studies Depression Scale (CES-D) were administered. Hypogonadal athletes were compared with eugonadal athletes as controls. MAIN OUTCOME MEASURES Prevalence and clinical symptoms of severe (TT < 8 nmol/L) or mild (8 nmol/L <or= TT < 12 nmol/L) testosterone deficiency were investigated. RESULTS The mean sample age was 61.9 +/- 7.5 years (range 50-75). Severe or mild testosterone deficiency was observed in 12% and 18%, respectively, of overall athletes, with the highest prevalence in athletes >70 years (27.5% and 25.0%, respectively). TT did not correlate with age, training duration, or questionnaire scores. No differences were observed for nonspecific symptoms of hypogonadism, IIEF-15 and CES-D scores between eugonadal and severe hypogonadal athletes. CONCLUSIONS Independently of its etiology, a significant percentage of aging athletes had undiagnosed testosterone deficiency. In a relevant number of these cases, testosterone deficiency was not overtly symptomatic. Our results suggest that sport-participation per se can influence the symptoms of hypogonadism. The history of clinical symptoms may be inaccurate to diagnose testosterone deficiency in aging athletes. Future research should address the clinical relevance and the specific risks of testosterone deficiency in aging athletes, and the need of a systematic pre-participation serum testosterone evaluation.

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), β-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 β-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 brains 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.

Concerns about serum androgens monitoring during testosterone replacement treatments in hypogonadal male athletes: a pilot study.

INTRODUCTION A well-tailored testosterone replacement treatment (TRT) in male hypogonadal athletes plays a pivotal role to restore physiological performances, to reduce health risks, and to guarantee the ethic of competition. Few studies evaluated individual androgens profiles during TRT in trained individuals. AIM The aim of this article was to verify the efficacy in restoring eugonadal serum and urinary androgens profiles after testosterone enanthate (TE) and gel (TG) administration. METHODS Ten male Caucasian-trained volunteers affected by severe hypotestosteronemia (<8 nmol/L) were included. Serum androgens and urinary testosterone metabolites were evaluated, in the same subjects, before and weekly for 5 weeks after both a single intramuscular TE injection (250 mg) and during a daily administration of TG (50 mg/die of testosterone), respectively. MAIN OUTCOME MEASURES The main outcome measures of this article were serum total testosterone (TT), dihydrotestosterone (DHT), calculated free and bioavailable testosterone (cFT, cBioT), 17-β-estradiol, and urinary glucuronide testosterone metabolites. RESULTS Supraphysiological TT concentrations were observed in 50% of our volunteers until 7 days after TE and in the 4% of total samples after TG. Serum DHT was high both after TE (all volunteers on day 7 and 50% on day 14) and during TG (32% of total samples). A relatively low number of samples showed normal cFT and cBioT both after TE and TG (20-44%, respectively). Urinary metabolites were related to the type of treatment and to serum androgens profile and resulted in the normal ranges from 15% to 60% of total samples. CONCLUSION Besides well-known variations of mean serum TT, we showed a high percentage of serum and urinary samples with abnormal androgens, being TG safer than TE. We conclude that monitoring TRT with TT only may be inaccurate because of abnormal fluctuations of other circulating androgens. Further studies to identify the appropriate markers of eugonadism during TRT are highly warranted both in athletes and in non-athletes.

Might erectile dysfunction be due to the thermolabile variant of methylenetetrahydrofolate reductase

Hyperhomocysteinemia is considered one of the most important cardiovascular risk factors increasing considerably the risk of stroke and myocardial infarction. With respect to endothelial function, direct effects of hyperhomocysteinemia on vascular endothelial cells have been demonstrated through the reduction of endothelial nitric oxide production. In this paper, we report the case of a young man with homozygote genotype mutated with 5-methylenetetrahydrofolate reductase (MTHFR) thermolabile variant who, in the absence of relational stress, developed an erectile dysfunction (ED) refractory to the vasoactive type-V phosphodiesterase (PDE5) inhibitor therapy. After one month of treatment with 5 mg/day folic acid and 1000 μg/day cyanocobalamin, the patient restarted the assumption of 50 mg sildenafil, obtaining satisfying erections during sexual intercourse. We suggest that hyperhomocysteinemia may interfere with penile blood supply and, thus, be responsible for ED. If this relationship is confirmed, plasma levels and urinary homocysteine (HCy) should be evaluated in selected young patients with vascular ED. Furthermore, careful attention should be given to the risk of ED when dealing with this metabolic disturbance.

Acute severe male hypo-testosteronemia affects central motor command in humans

PURPOSE To indirectly evaluate the effect of androgens on neuromuscular system in humans we analyzed if an induced short-term hypogonadal state (serum total testosterone-TT<2.3ng/ml) may affect central drive to skeletal muscle and/or muscle neuro-mechanical performance. METHODS We compared voluntary and electrically evoked muscle sEMG signals from biceps brachii in nine hypogonadal male volunteers (Hypo) and in ten healthy controls (Cont). Serum TT and dihydrotestosterone (DHT) were assayed. RESULTS With respect to Hypo, Cont exhibited significantly higher median frequency content (MDF) at any angular velocity; normalized MDF [95.9% (SD=23.3) vs 73.8% (SD=9.3)]; muscle fiber conduction velocity (CV) from lowest to highest angular velocities; initial MDF at fatigue test [91.78Hz (SD=22.03) vs 70.94Hz (SD=11.06)] as well as was the normalized slope [-0.64 (SD=0.14 vs -0.5 (SD=0.11)]. In the non-fatigued state, Hypo showed a slower single twitches time to peak (TTP). In Cont, half relaxation time (HRT) decreased after fatigue while increased in Hypo (p<0.05 between groups). A significant correlation between both TT and dihydrotestosterone with MDF and CV was found during voluntary contractions only. CONCLUSIONS A brief exposure to very low serum TT concentration in males seem to determine a reduced excitability of the NM system which, in turn, would favor a predominant recruitment of slow twitch MUs.

Urinary and serum hormones profiles after testosterone enanthate administration in male hypogonadism: concerns on the detection of doping with testosterone in treated hypogonadal athletes.

Objective: To describe serum and urinary hormones, androgens metabolites and testosterone/epitestosterone ratio profiles after testosterone administration in male hypogonadal volunteers, and to evaluate their possible usefulness in detecting doping with testosterone in treated hypogonadal athletes. Design: Controlled open label design vs placebo; pharmacokinetic study. Participants: Ten male volunteers affected by severe hypogonadism (serum testosterone <2.31 ng/ml). Interventions and main outcome measures: Serum and urinary parameters were evaluated, by radioimmunoassay and gas chromatography-mass spectrometry, before and at different time points for 7/3 weeks after a single administration of testosterone enanthate (250 mg) or placebo, respectively. Results: As partially known, testosterone administration increased, with great individual variability, urinary concentrations of glucuronide testosterone, androsterone, etiocholanolone, 5α-androstane-3α,17β-diol, 5β-androstane-3α,17β-diol, testosterone/epitestosterone and testosterone/LH ratios; and decreased epitestosterone and 5α-androstane-3β,17β-diol/5β-an-drostane-3α,17β-diol ratio. Serum testosterone and dihydrotestosterone increased in all volunteers, and concentrations higher than the upper reference limits were observed in many volunteers until 2 weeks after testosterone administration. Conclusion: Whereas the observed prolonged hyperandrogenism partially limited data interpretation, the reported characteristics of variation of urinary parameters might be used to suspect testosterone misuse in hypogonadal athletes treated with testosterone enanthate. In this sense, while the actual threshold for testosterone/epitestosterone ratio was confirmed to be of reduced usefulness, we suggest a contemporary evaluation of whole urinary androgen metabolites profile and serum androgens, at specific time points after testosterone enanthate administration. Moreover, an adequate tailoring of treatment, to avoid transitory hyperandrogenism, is highly advisable. Further studies on strategies for detecting doping with testosterone in hypogonadal athletes are warranted.