Tadalafil improves lean mass and endothelial function in nonobese men with mild ED/LUTS: in vivo and in vitro characterization

PURPOSE: Phosphodiesterase type-5 inhibitor administration in diabetic men with erectile dysfunction (ED) is associated with reduced waist circumference. We evaluated potential effects of daily tadalafil administration on body composition and investigated its possible mechanism(s) of action in C2C12 skeletal muscle cells in vitro. METHODS: Forty-three men on stable caloric intake (mean age 48.5 ± 7; BMI 25.5 ± 0.9 kg/m2) complaining mild ED and/or low urinary tract symptoms (LUTS) were randomly assigned to receive tadalafil (TAD) 5 mg/daily (once-a-day=OAD-TAD; n = 23) or 20 mg on-demand (on-demand=OD-TAD; n = 20) for 2 months. Primary outcomes were variations of body composition measured by Dual-energy X-ray absorptiometry; secondary outcomes were ED/LUTS questionnaire scores along with hormone (testosterone, estradiol, insulin) and endothelial function (Endopat2000) variations. RESULTS: OAD-TAD increased abdominal lean mass (p < 0.01) that returned to baseline after 2 months withdrawal. LUTS scores improved (p<0.01) in OD-TAD while ED scores improved (p < 0.01) in both groups. We found significant improvements in endothelial function (p < 0.05) that directly correlated with serum insulin (p < 0.01; r = 0.3641) and inversely correlated with estradiol levels (p < 0.01; r = 0.3655) even when corrected for potential confounders. Exposure of C2C12 cells upon increasing tadalafil concentrations (10-7 to 10-6 M) increased total androgen receptor mRNA and protein expression as well as myogenin protein expression after 24 and 72 h (2.8 ± 0.4-fold and 1.4 ± 0.02-fold vs. control, respectively, p < 0.05). CONCLUSIONS: Daily tadalafil improved lean mass content in non-obese men probably via enhanced insulin secretion, estradiol reduction, and improvement of endothelial function in vivo. The in vitro increased myogenin and androgen receptor protein expression in skeletal muscle cells suggests a translational action of phosphodiesterase type-5 on this receptor

Osteoporosis and Sarcopenia Increase Frailty Syndrome in the Elderly

Musculoskeletal aging is a major public health interesting and strain due to the significant demographic modifications in the population, and it is linked to high risk of falls, loss of autonomy in elderly individuals and institutionalization with small health outcomes. Thus, this pathological status is related to high morbidity and health care rates. Bone mass and muscle mass and strength increase during late adolescence and early adulthood but start to reduce noticeably from the fifth decade of life and are closely linked. Bone and muscle tissues were increasingly recognized, as endocrine target organs and endocrine organs themselves, interacting through paracrine and endocrine signals. During growth, bone mineral content closely correlates with muscle mass, and several evidences suggest that osteoporosis and sarcopenia present common pathophysiological factors and show the correlation between low bone mineral density and sarcopenia in both men and women. Then, sarcopenia and osteoporosis, typical features of aging, are often associated with each other and with the frailty syndrome. In particular, sarcopenia and osteoporosis are major contributors to disability and frailty and the common denominators are age-related chronic inflammation, changes in body composition and hormonal imbalance. Frailty syndrome is characterized by a reduced response to stress, triggering the decline of the physiological functioning of the various systems. Frailty syndrome, typical of the older people, is frequently associated with a reduction in the quality of life and mobility. Falls often are the basis of reduced mobility and ability to perform the common functions of daily life and the increase in the number of institutionalizations. Moreover, the reduction of muscle mass, associated with altered muscle composition, fat and fibrous infiltration and alterations in innervations, and the increase in fat mass, have a synergistic effect on the increase in cardiovascular risk. The aim of this review is to analyze the pathophysiological mechanisms underlying the frailty syndrome and its association with sarcopenia and osteoporosis, and investigate possible intervention measures

Trunk Fat Negatively Influences Skeletal and Testicular Functions in Obese Men: Clinical Implications for the Aging Male

Osteocalcin (OSCA) seems to act as a negative regulator of energy metabolism and insulin sensitivity. Evidence from male rodents suggests that OSCA may also regulate testosterone (T) synthesis. Using a cross-sectional design, we evaluated OSCA, 25(OH) vitamin D, T, 17β-estradiol (E2), homeostasis model assessment of insulin resistance (HOMA-IR), and body composition in 86 obese (mean BMI = 34) male subjects (18–69 yr old). Independently from BMI, an inverse relationship between trunk fat percentage and plasma T (r2=−0.26, P<0.01) and between HOMA-IR and OSCA levels (r2=−0.22, P<0.005) was found. OSCA levels, as well as vitamin D, decreased significantly for higher BMI with significant differences above 35 (P<0.01). A direct correlation between T and bone mineral density at lumbar (BMDL) and neck (BMDH) (P<0.001, r2=−0.20; P<0.001, r2=−0.24) was found, independently from age. An inverse correlation between E2 levels, BMDL, and BMDH (P<0.001, r2=−0.20; P<0.001, r2=−0.19) was observed. These data provide new evidences that a relationship between trunk fat mass, insulin sensitivity, OSCA and T synthesis occurs. This new relationship with skeletal health has relevant implications for the aging male, suggesting OSCA as a novel marker of metabolic and gonadal health status

Molecular Mechanisms Generating and Stabilizing Terminal 22q13 Deletions in 44 Subjects with Phelan/McDermid Syndrome

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17–74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81&nbsp;years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Androgen deficiency and hormone-replacement therapy

[No abstract available

CAG repeat testing of androgen receptor polymorphism: is this necessary for the best clinical management of hypogonadism?

Introduction It is controversial whether or not testing the length of the androgen receptor polymorphism in clinical practice is useful for correct diagnosis and treatment of hypogonadism. AimTo describe the molecular and clinical implications of testing the length of the androgen receptor polymorphism for treatment of hypogonadism in both male and female subjects. MethodsA systematic Medline search was conducted using several terms related to and including the terms androgen receptor, CAG-repeat polymorphism, male hypogonadism, female hypogonadism, and neurodegenerative disease. Main Outcome MeasuresClinical evidence that demonstrates the importance of CAG repeat number investigation in male and female hypogonadism. Results A thorough review of the clinical utility of CAG repeat polymorphism investigation in men and women with hypogonadism is presented. Conclusions The role of AR CAG repeat number investigation in hypogonadism (male and female) is not yet established in the clinical practice. In both sexes, a role during clinical management of hormonal replacement therapies may be hypothesized, but the CAG repeat number's relationship with the presence or absence of hypogonadal symptoms remains unclear. Pharmacogenomic investigations of the AR polymorphism may be a future option to tailor testosterone titration individually and to better identify subjects as potentially more or less responsive to treatments; also, investigation may be important to individually predict beneficial and side effects in special subpopulations, specifically, obese men and postmenopausal women. Francomano D, Greco EA, Lenzi A, and Aversa A. CAG repeat testing of androgen receptor polymorphism: Is this necessary for the best clinical management of hypogonadism? J Sex Med 2013;10:2373-2381