Influence of androgen receptor CAG polymorphism on sexual function recovery after testosterone therapy in late-onset hypogonadism.

INTRODUCTION: Androgen receptor (AR) CAG polymorphism has been found to influence sexual function. However, no study has evaluated its potential to condition sexual function recovery after testosterone replacement therapy (TRT) in a large cohort of hypogonadic subjects. AIM: To evaluate the role of this polymorphism in sexual function improvement after TRT in late-onset hypogonadism (LOH). METHODS: Seventy-three men affected by LOH were retrospectively considered. Evaluations were performed before TRT started (time 0) and before the sixth undecanoate testosterone injection. MAIN OUTCOME MEASURES: International Index of Erectile Function (IIEF) questionnaire (erectile function [EF], orgasmic function [OF], sexual desire [SD], intercourse satisfaction [IS], overall satisfaction [OS], and total IIEF-15 score); total and free testosterone and estradiol; AR gene CAG repeat number. RESULTS: TRT induced a significant increase in total and free testosterone and estradiol. All IIEF domains significantly improved after TRT. AR CAG repeats negatively and significantly correlated with all the variations (Δ-) of sexual function domains, except for Δ-OS. Conversely, Δ-total testosterone was found to be positively and significantly correlated with sexual function domain variations, except for Δ-IS and Δ-OS. Δ-estradiol did not correlate significantly with any of the variations of sexual function domains. After inclusion in generalized linear models, the number of AR gene CAG triplets was found to be independently and negatively associated with Δ-EF, Δ-SD, Δ-IS, and Δ-Total IIEF-15 score, whereas Δ-total testosterone was independently and positively associated with Δ-EF, Δ-OF, Δ-SD, and Δ-Total IIEF-15 score. However, after including time 0 total testosterone in the model, AR gene CAG triplets remained independently and negatively associated only with Δ-EF and Δ-Total IIEF-15 score, whereas Δ-total testosterone was independently and positively associated only with Δ-EF. CONCLUSIONS: Longer length of AR gene CAG repeat tract seems to lower TRT-induced improvement of sexual function in LOH.

Increased levels of osteocalcin-positive endothelial progenitor cells in patients affected by erectile dysfunction and cavernous atherosclerosis.

INTRODUCTION: Erectile dysfunction (ED) was shown to be the expression of a systemic vascular disease that can precede coronary artery disease of some years. Endothelial progenitor cells (EPCs) are a population of circulating cells with endothelial-regenerative potential that may be reduced in ED and coronary patients. Recently, increased levels of osteocalcin (OCN)-positive EPC have been reported in coronary patients. AIM: Investigate the correlation between OCN-positive EPC and cavernous atherosclerotic lesion in ED patients. METHODS: A total of 35 subjects (20 ED patients and 15 controls) were evaluated in our andrological center and enrolled in the study. MAIN OUTCOME MEASURE: All subjects underwent routine clinical examination. Patients were also evaluated with high resolution echo color doppler of penile districts (intima media thickness [IMT] before and after intracavernous alprostadil injection) and circulating levels of progenitor cells (PC), EPC, and OCN-positive fraction of EPC. RESULTS: A progressive reduction of circulating EPC with the severity of cavernous artery atherosclerosis was found. Conversely circulating OCN-positive EPC levels undergo to a significant increase with cavernous atherogenesis progression. CONCLUSIONS: OCN-positive EPC levels in association with penile-color Doppler ultrasound evaluation of cavernous IMT could be predictive markers of subsequent coronary artery disease in ED patients.

Impella in cardiogenic shock following acute myocardial infarction: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Cardiogenic shock (CS) conveys a high mortality risk. A cardiac assist device may serve as bridge to patient recovery. We aimed to provide a pooled estimate on mortality and complications from studies evaluating the use of the left ventricular assist device Impella in CS following acute myocardial infarction. In addition, we evaluated whether mortality risk differed with device placement before or after percutaneous coronary intervention (PCI). METHODS: We searched Medline, Embase and Web of Science from 2005 until July 2019 for observational studies or clinical trials on this specific patient group. Studies were required to report on 30-day all-cause mortality and device-related complications. We calculated pooled proportions with 95% confidence intervals (CI) using random effects models and the inverse variance method. RESULTS: Overall, 671 patients from 11 studies (2 randomized and 9 observational) were included. Pooled proportions showed a 30-day mortality of 54.6% (95% CI 47.3-61.8; P = 0.22; I2 = 65.8%). Among complications, major bleeding was found in 19.9% (95% CI 14.2-27.3; P < 0.05; I2 = 69.1%), hemolysis in 10.5% (95% CI 7.2-15.0; P < 0.05; I2 = 52.1%), limb ischemia in 5.0% (95% CI 2.6-9.5; P < 0.05; I2 = 48.3%) and stroke in 3.8% of patients (95% CI 2.4-5.9; P < 0.05; I2 = 0%). Sensitivity analysis demonstrated a statistically significant risk reduction in 30-day mortality when Impella was implanted prior to PCI as compared to after PCI, risk ratio (RR): 0.71, CI 0.58-0.86, P = 0.001, I2 = 0%. CONCLUSION: Pooled estimates of Impella use in myocardial infarction with CS revealed a high 30-day mortality; however, as compared to post-PCI, Impella initiation prior to PCI was associated with a survival benefit.

Reduced endothelial progenitor cell number and function in inflammatory bowel disease: a possible link to the pathogenesis.

OBJECTIVES: Circulating endothelial progenitor cells (EPCs) are essential for endothelial repair and vascular healing. Patients with inflammatory bowel disease (IBD) may suffer from endothelial dysfunction. Reduced EPC number, impaired mobilization, or increased EPC apoptosis may be crucial in this phenomenon. The aim of our study was to investigate the number and function of EPCs in patients with IBD and to assess their endothelial function. METHODS: In 100 IBD patients (47 ulcerative colitis (UC) and 53 Crohn's disease (CD)) and 50 healthy controls, EPC number, CXC motif receptor 4 (CXCR4) expression, the percentage of apoptotic circulating EPCs, and the number of colony-forming units were evaluated. Endothelial dysfunction was assessed by luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone levels, and in a subgroup of patients, brachial artery flow-mediated dilation (FMD) was measured. Kruskal-Wallis ANOVA (analysis of variance), Mann-Whitney U two-tailed, and Spearman's rank correlation tests were used to assess differences. RESULTS: EPC number was significantly lower in UC patients (39.6 (95% confidence interval (95% CI): 30.7-48.6)) and in CD patients (43.1 (95% CI: 35.9-50.4)) than in healthy controls (97.1 (95% CI: 88.3-105.9)), (P<0.001). LH and FSH levels and CXCR4 expression on EPCs did not significantly differ from controls. Testosterone concentrations and FMD were lower in UC patients. Number of apoptotic EPCs was higher in both UC and CD patients with an impaired ability to generate colony in vitro. CONCLUSIONS: We hypothesize that in IBD patients, apoptosis contributes to the reduction of circulating EPC number and to their ability to proliferate in vitro. As this condition represents a risk factor for cardiovascular disease, endothelial function should be evaluated in these patients.

Oestrogen stimulates endothelial progenitor cells via oestrogen receptor-alpha.

CONTEXT: Oestrogens play an important protective role on the vascular system. The endothelial cell layer is a direct target for these hormones, and expresses at least two oestrogen receptors, ER-alpha and ER-beta. Recent studies have shown that vascular healing is significantly modulated by circulating bone marrow-derived cells. A subset of these stem cells, endothelial progenitor cells (EPCs), have recently been described as a population of pluripotent cells within the peripheral blood capable of differentiating into endothelial cells. OBJECTIVE: In the present study we investigated the expression of ER-alpha and ER-beta on human EPCs and the effect that oestrogens have on the function of EPCs in vitro. METHODS: EPCs were isolated and cultured from healthy donors. RT-PCR, western blotting and immunohistochemistry were used to assess expression of ER-alpha and ER-beta. Proliferation and CFU assays were used to assess the response of EPCs to different doses of 17,beta-oestradiol. MAIN OUTCOME MEASURES: Expression of ER-alpha and ER-beta in EPCs, and the effect of 17,beta-oestradiol on proliferation of EPCs. RESULTS: Human EPCs express ER-alpha mRNA and protein. 17,beta-oestradiol increases proliferation of EPCs and CFU in a dose-dependent manner. CONCLUSIONS: Human EPCs express ER-alpha but not ER-beta, and oestrogens can stimulate the proliferation of these cells in vitro. Oestrogens exert these effects at concentrations that are usually reached during stimulation for in vitro fertilization in women, and therefore further studies are needed to clarify the clinical significance of these effects.

Relationship between vascular damage degrees and endothelial progenitor cells in patients with erectile dysfunction: effect of vardenafil administration and PDE5 expression in the bone marrow.

OBJECTIVES: To evaluate the levels of circulating progenitor cells (PCs) and the effect of a single dose of vardenafil 20mg on the number of these cells in men with erectile dysfunction (ED) and various degree of vascular injury at the carotid artery level. METHODS: Sixty-eight patients with ED and various degree of carotid damage, and 25 controls were enrolled. Patients were divided into three groups according to their intima media thickness (IMT) status (normal, mild increase, or plaque). All subjects received vardenafil 20mg, and evaluation of the number of circulating PCs was performed at baseline and 4h after vardenafil administration. An RNA expression analysis of phosphodiesterase type 5 (PDE5) on bone marrow was also performed. RESULTS: We found a significant reduction of circulating PCs in ED patients with respect to controls and a reduction in PC counts in patients with mild IMT increase or plaque, but not in those with normal IMT. Four hours after vardenafil administration we observed an increase in the number of PCs in all patients and controls. Reverse transcriptase-polymerase chain reaction analysis showed that human bone marrow expresses PDE5 messenger RNA. CONCLUSIONS: Patients with ED and a low number of circulating PCs may be considered at increased risk for an endothelial dysfunction. An impaired response to vardenafil stimulus may be proposed as a surrogate marker of a patient's endothelial regenerative ability.