Publications by authors named "Davide Francomano"

30 Publications

  • Page 1 of 1

The Role of Antioxidants Supplementation in Clinical Practice: Focus on Cardiovascular Risk Factors.

Antioxidants (Basel) 2021 Jan 20;10(2). Epub 2021 Jan 20.

Faculty of Medicine and Surgery, Sapienza University of Rome, 04100 Latina, Italy.

Oxidative stress may be defined as an imbalance between reactive oxygen species (ROS) and the antioxidant system to counteract or detoxify these potentially damaging molecules. This phenomenon is a common feature of many human disorders, such as cardiovascular disease. Many of the risk factors, including smoking, hypertension, hypercholesterolemia, diabetes, and obesity, are associated with an increased risk of developing cardiovascular disease, involving an elevated oxidative stress burden (either due to enhanced ROS production or decreased antioxidant protection). There are many therapeutic options to treat oxidative stress-associated cardiovascular diseases. Numerous studies have focused on the utility of antioxidant supplementation. However, whether antioxidant supplementation has any preventive and/or therapeutic value in cardiovascular pathology is still a matter of debate. In this review, we provide a detailed description of oxidative stress biomarkers in several cardiovascular risk factors. We also discuss the clinical implications of the supplementation with several classes of antioxidants, and their potential role for protecting against cardiovascular risk factors.
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http://dx.doi.org/10.3390/antiox10020146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909411PMC
January 2021

Sperm Parameters before and after Swim-Up of a Second Ejaculate after a Short Period of Abstinence.

J Clin Med 2020 Apr 5;9(4). Epub 2020 Apr 5.

Department of Clinical and Experimental Medicine, University of Catania, 95125, Catania, Italy.

Background: Recent studies have supported the beneficial effects of a short abstinence period on sperm parameters. The aim of this study was to assess sperm motility, morphology and DNA fragmentation before and after swim-up of a second ejaculate obtained after a short abstinence period in normozoospermic men and oligo-astheno-teratozoospermic (OAT) patients.

Material And Methods: Semen analyses and swim-up preparations of two consecutive semen samples (collected within 1 h) were carried out in 30 normozoospermic and 35 OAT patients enrolled in an assisted reproductive technique (ART) program.

Results: Compared to the first ejaculate, the second sample showed a higher percentage of spermatozoa with normal form ( < 0.01) and lower percentage of spermatozoa with DNA fragmentation ( < 0.01) in normozoospermic men, whereas a higher percentage of spermatozoa with progressive motility ( < 0.001) and normal morphology ( < 0.0001) was found in OAT patients. Swim-up separation showed a lower DNA fragmentation rate ( < 0.05) in the second ejaculate in normozoospermic men, whereas the second ejaculate of OAT patents showed an increase in normally-shaped spermatozoa ( < 0.01) and lower percentage of spermatozoa with fragmented DNA ( < 0.001) compared to the first one.

Conclusions: Swim-up separation of a second ejaculate collected within 1 h might be suggested for ART procedures, especially in OAT patients.
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http://dx.doi.org/10.3390/jcm9041029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231087PMC
April 2020

Mangosteen Extract Shows a Potent Insulin Sensitizing Effect in Obese Female Patients: A Prospective Randomized Controlled Pilot Study.

Nutrients 2018 May 9;10(5). Epub 2018 May 9.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, Sapienza University of Rome, 00161 Rome, Italy.

There is a widely acknowledged association between insulin resistance and obesity/type 2 diabetes (T2DM), and insulin sensitizing treatments have proved effective in preventing diabetes and inducing weight loss. Obesity and T2DM are also associated with increased inflammation. Mangosteen is a tropical tree, whose fruits—known for their antioxidant properties—have been recently suggested having a possible further role in the treatment of obesity and T2DM. The objective of this pilot study has been to evaluate safety and efficacy of treatment with mangosteen extract on insulin resistance, weight management, and inflammatory status in obese female patients with insulin resistance. Twenty-two patients were randomized 1:1 to behavioral therapy alone or behavioral therapy and mangosteen and 20 completed the 26-week study. The mangosteen group reported a significant improvement in insulin sensitivity (homeostatic model assessment-insulin resistance, HOMA-IR −53.22% vs. −15.23%, = 0.004), and no side effect attributable to treatment was reported. Given the positive preliminary results we report and the excellent safety profile, we suggest a possible supplementary role of mangosteen extracts in the treatment of obesity, insulin resistance, and inflammation.
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http://dx.doi.org/10.3390/nu10050586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986466PMC
May 2018

Effect of the GSTM1 gene deletion on glycemic variability, sympatho-vagal balance and arterial stiffness in patients with metabolic syndrome, but without diabetes.

Diabetes Res Clin Pract 2018 Apr 13;138:158-168. Epub 2018 Feb 13.

Endocrinology, Diabetes and Metabolism, S. Giovanni Calibita Fatebenefratelli Hospital, Dept. of Systems Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address:

Aims: An increased rate of cerebrovascular complications in patients with metabolic syndrome (MetS) has been reported. Previous studies demonstrated an association between glycemic variability (GV) and cerebrovascular reactivity (CRV) in MetS, thus suggesting a putative role of GV on cerebrovascular events. Although the pathophysiological mechanism linking GV to damage is still to be elucidated, evidence suggests oxidative stress plays a crucial role. Since functional variants in glutathione S-transferases (GST) genes modulate the cellular detoxification processes, the aim of this study was to elucidate the involvement of GSTs in MetS and investigating the correlation with GV, arterial stiffness, and sympatho-vagal (SV) balance.

Methods: A hundred metabolic syndrome patients without diabetes underwent GST gene polymorphism analysis and a sub-sample 36 patients were randomly selected to investigate the correlation between GST gene polymorphisms and GV, and sympatho-vagal (SV) balance and arterial stiffness.

Results: GSTM1 showed a significant association with several GV, arterial stiffness, and SV balance indexes. In particular, the GSTM1 deletion positively correlates with lower values of these indexes when compared to the presence of the gene.

Conclusions: Therefore, we suggested a global influence of GSTM1 deletion on the GV, arterial stiffness, and SV balance pathways in MetS patients, probably also interacting with AMP-activated protein kinase (AMPK) regulation. Our novel findings indicate GSTM1 could be a risk locus in MetS development and shed light novel scenarios on the role of glucose fluctuations in neurological impairments.
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http://dx.doi.org/10.1016/j.diabres.2018.02.006DOI Listing
April 2018

Insulin growth factor-1 correlates with higher bone mineral density and lower inflammation status in obese adult subjects.

Eat Weight Disord 2018 Jun 7;23(3):375-381. Epub 2017 Mar 7.

Department of Movement, Human and Health Sciences, Section of Health Sciences, University "Foro Italico", Largo Lauro De Bosis 6, 00135, Rome, Italy.

Purpose: Obesity is a severe public health problem worldwide, leading to an insulin-resistant state in liver, adipose, and muscle tissue, representing a risk factor for type 2 diabetes mellitus, cardiovascular diseases, and cancer. We have shown that abdominal obesity is associated with homeostasis derangement, linked to several hormonal and paracrine factors. Data regarding potential link between GH/IGF1 axis, bone mineral density, and inflammation in obesity are lacking. Thus, aim of this study was to evaluate correlation among IGF-1, BMD, and inflammation in obese individuals.

Methods: The study included 426 obese subjects, mean age 44.8 ± 14 years; BMI 34.9 ± 6.1. Exclusion criteria were chronic medical conditions, use of medications affecting bone metabolism, hormonal and nutritional status, recent weight loss, and prior bariatric surgery. Patients underwent measurements of BMD and body composition by DEXA and were evaluated for hormonal, metabolic profile, and inflammatory markers.

Results: In this population, IGF-1 was inversely correlated with abdominal FM% (p < 0.001, r  = 0.12) and directly correlated with osteocalcin (OSCA) (p < 0.002, r  = 0.14). A negative correlation was demonstrated between IGF-1 levels and nonspecific inflammatory index, such as fibrinogen (p < 0.01, r  = 0.04) and erythrocyte sedimentation rate (p < 0.0001, r  = 0.03). IGF-1 was directly correlated with higher BMD, at both lumbar (p < 0.02, r  = 0.03) and femoral site (p < 0.04, r  = 0.03).

Conclusions: In conclusion, our results show that higher levels of serum IGF-1 in obese patients correlate with lower inflammatory pattern and better skeletal health, as demonstrated by higher BMD and osteocalcin levels. These results lead to speculate the existence of a bone-adipose-muscle interplay modulating energy homeostasis, glucose, bone metabolism, and chronic inflammation in individuals affected by abdominal obesity.
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http://dx.doi.org/10.1007/s40519-017-0362-4DOI Listing
June 2018

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

Endocrine 2017 Jun 30;56(3):639-648. Epub 2017 Jan 30.

Department of Movement, Human and Health Sciences, Section of Health Sciences, "Foro Italico" University of Rome, Rome, Italy.

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 CC skeletal muscle cells in vitro.

Methods: Forty-three men on stable caloric intake (mean age 48.5 ± 7; BMI 25.5 ± 0.9 kg/m) 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 CC cells upon increasing tadalafil concentrations (10 to 10 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.
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http://dx.doi.org/10.1007/s12020-016-1208-yDOI Listing
June 2017

Natural antioxidant ice cream acutely reduces oxidative stress and improves vascular function and physical performance in healthy individuals.

Nutrition 2017 Jan 26;33:225-233. Epub 2016 Jul 26.

Department of Experimental Medicine, Section of Medical Pathophysiology, Food Science and Endocrinology, "Sapienza" University of Rome, Rome, Italy.

Objective: The formation of reactive oxygen species (ROS) contributes to the pathogenesis and progression of several diseases. Polyphenols have been shown to be beneficial against ROS. The aim of this study was to evaluate the effects of a natural antioxidant ice cream on oxidative stress, vascular function, and physical performance.

Methods: In this controlled, single-blind, crossover study, 14 healthy individuals were randomized to consume 100 g of either antioxidant ice cream containing dark cocoa powder and hazelnut and green tea extracts or milk chocolate ice cream (control ice cream). Participants were studied at baseline and 2 h after ingesting ice cream. Serum polyphenols, antioxidant status (ferric-reducing ability of plasma [FRAP]), nitric oxide (NOx) bioavailability, markers of oxidative stress (determination of reactive oxygen metabolites [d-ROMs] and hydrogen peroxide [HO]), endothelium function (flow-mediated dilation [FMD] and reactive hyperemia index [RHI]), and exercise tolerance (stress test) were assessed, and the double product was measured.

Results: Serum polyphenols (P < 0.001), NOx (P < 0.001), FRAP (P < 0.005), FMD (P < 0.001), and RHI (P < 0.05) increased significantly, oxidative stress decreased (d-Roms, P < 0.001; HO, P < 0.001), and the double product (P < 0.001) was improved only after antioxidant ice cream ingestion. No changes were found after control ice cream ingestion.

Conclusions: To our knowledge, this is the first study to demonstrate that a natural ice cream rich in polyphenols acutely improved vascular function and physical performance in healthy individuals through a reduction in oxidative stress.
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http://dx.doi.org/10.1016/j.nut.2016.07.008DOI Listing
January 2017

Is late-onset hypogonadotropic hypogonadism a specific age-dependent disease, or merely an epiphenomenon caused by accumulating disease-burden?

Minerva Endocrinol 2016 Jun 17;41(2):196-210. Epub 2016 Feb 17.

Endocrinology Unit, Azienda USL di Bologna, Medical Department, Maggiore-Bellaria Hospital, Bologna, Italy -

Background: The aim of this paper is to summarize the available evidence supporting the link between late onset hypogonadism (LOH) and associated common clinical illnesses, focusing on metabolic diseases. The possible benefits or risks related to testosterone replacement therapy (TRT) in these conditions will also be analyzed.

Methods: An extensive Medline search was performed.

Results: LOH is closely associated with a worse metabolic profile and a higher cardiovascular risk. The relationship between hypogonadism obesity and insulin resistance is complex and bidirectional. Emerging evidence suggests a positive role of TRT in improving body composition and metabolic outcomes in subjects with LOH.

Conclusions: Despite the aforementioned data, it is not completely known whether reduced testosterone levels in elderly males might play a direct pathogenetic role in these conditions or whether low T and associated morbidities are concomitant conditions, both associated with the aging process. Further and longer studies are advisable to confirm the preliminary results.
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June 2016

Tadalafil reduces visceral adipose tissue accumulation by promoting preadipocytes differentiation towards a metabolically healthy phenotype: Studies in rabbits.

Mol Cell Endocrinol 2016 Mar 19;424:50-70. Epub 2016 Jan 19.

Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences, Viale Morgagni 50, 50134, University of Florence, Florence, Italy. Electronic address:

Development of metabolically healthy adipocytes within dysfunctional adipose tissue may represent an attractive way to counteract metabolic syndrome (MetS). In an experimental animal model of high fat diet (HFD)-induced MetS, in vivo, long- and short-term tadalafil treatments were able to reduce visceral adipose tissue (VAT) accumulation and hypertriglyceridemia, and to induce the expression in VAT of the brown fat-specific marker, uncoupling protein 1 (UCP1). VAT preadipocytes (PAD), isolated from the tadalafil-treated HFD rabbits, showed: i) a multilocular morphology; ii) an increased expression of brown fat-specific genes (such as UCP1 and CIDEA); iii) improved mitochondrial structure and dynamic and reduced superoxide production; iv) improved insulin sensitivity. Similar effects were obtained after in vitro tadalafil treatment in HFD rPAD. In conclusion, tadalafil counteracted HFD-associated VAT alterations, by restoring insulin-sensitivity and prompting preadipocytes differentiation towards a metabolically healthy phenotype.
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http://dx.doi.org/10.1016/j.mce.2016.01.015DOI Listing
March 2016

Does testosterone supplementation increase PDE5-inhibitor responses in difficult-to-treat erectile dysfunction patients?

Expert Opin Pharmacother 2015 Apr 3;16(5):625-8. Epub 2015 Feb 3.

Department of Experimental Medicine, Medical Pathophysiology, Food and Science and Endocrinology Section,"Sapienza" University of Rome, Viale Regina Elena , 324, 00161 Rome , Italy +39 06 49970721 ; +39 06 4461450 ;

Introduction: Men with erectile dysfunction (ED) considered challenging-to-treat with PDE-5 inhibitors (PDE5i) include patients with severe neurological damage (e.g., due to radical prostatectomy), diabetes and severe vascular disease. Another factor that may limit PDE5i efficacy is the age-related decline of testosterone (T), occurring in 3 - 35% of older men depending on different cut-offs chosen. T regulation of PDE5 expression has been accepted as one of the major mechanisms controlling vasodilator mechanisms in penile tissue.

Areas Covered: We reviewed data regarding the use of T as a salvage therapy in PDE5i nonresponders.

Expert Opinion: Guidelines recommend that hypogonadal men with ED should commence therapy with PDE5i due to time course effects of T on erection that needs 6 - 12 weeks to occur. The possibility to 'salvage' some patients with low T not responding to PDE5i alone by adding T therapy should consider correct cut-off values, plasma T levels attained and androgen receptor (AR) polymorphism. Meta-analyses suggest that T treatment plus PDE5i yielded more effective results in noncontrolled versus controlled studies. We recommend T assay in all men with ED not responsive to PDE5i. Before commencing T treatment, side effects and consequent higher mortality in older frail men have to be avoided.
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http://dx.doi.org/10.1517/14656566.2015.1011124DOI Listing
April 2015

Erectile dysfunction in the elderly: an old widespread issue with novel treatment perspectives.

Int J Endocrinol 2014 17;2014:878670. Epub 2014 Mar 17.

Department of Science of Health, School of Medicine, University "Magna Græcia" of Catanzaro, 88100 Catanzaro, Italy ; Psychiatry Unit, "Mater Domini" University Hospital, 88100 Catanzaro, Italy.

Erectile dysfunction (ED) is one of the most common chronic diseases affecting men and its prevalence increases with aging. It is also the most frequently diagnosed sexual dysfunction in the older male population. A number of different diseases potentially worsening sexual function may occur in elderly people, together with polypharmacy. Related causes of ED are variable and can include arterial, neurogenic, hormonal, cavernosal, iatrogenic, and psychogenic causes. The aim of the present review was to examine the main aspects of erectile dysfunction going through epidemiology and pathophysiology and revise most of ED in elderly disabled men and in those affected with psychiatric disorders. Lastly we tried to focus on the main aspects of nonpharmacological and pharmacological treatments of ED and the recreational use in the elderly. Phosphodiesterase-5 inhibitors (PDE5-I) are commonly used for on-demand or chronic treatment of ED. It is widely known that PDE5-I have lower response rates in older men than in younger patients, but they have the advantages of ease of use and excellent safety profile, also in the elderly. The old and new PDE5-I as well as the alternative treatments for ED are extensively discussed.
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http://dx.doi.org/10.1155/2014/878670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976909PMC
June 2014

Effects of five-year treatment with testosterone undecanoate on metabolic and hormonal parameters in ageing men with metabolic syndrome.

Int J Endocrinol 2014 12;2014:527470. Epub 2014 Feb 12.

Department of Experimental Medicine, Medical Pathophysiology, Food Science and Endocrinology Section, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.

Metabolic and hormonal modifications after long-term testosterone (T) treatment have never been investigated. 20 hypogonadal men (mean T = 241 ng/dL-8.3 nmol/L) with metabolic syndrome (MS, mean age 58) were treated with T-undecanoate injections every 12 weeks for 60 months. 20 matched subjects in whom T was unaccepted or contraindicated served as controls. Primary endpoints were variations from baseline of metabolic and hormonal parameters. In T-group, significant reductions in waist circumference (-9.6 ± 3.8 cm, P < 0.0001), body weight (-15 ± 2.8 Kg, P < 0.0001), and glycosylated hemoglobin (-1.6  ±  0.5%, P < 0.0001) occurred, along with improvements in insulin sensitivity (HOMA-I; -2.8  ±  0.6, P < 0.0001), lipid profile (total/HDL-cholesterol ratio -2.9 ± 1.5, P < 0.0001), systolic and diastolic blood pressure (-23 ± 10 and -16 ± 8 mm Hg, P < 0.0001, resp.), and neck and lumbar T-scores (+0.5 ± 0.15 gr/cm(2), P < 0.0001; +0.7 ± 0.8, P < 0.0001, resp.). Also, serum vitamin D (+14.0 ± 1.3 ng/mL, P < 0.01), TSH (- 0.9 ± 0.3 mUI/mL, P < 0.01), GH (0.74 ± 0.2 ng/mL, P < 0.0001), and IGF1 (105 ± 11 ng/mL, P < 0.01) levels changed in T-group but not in controls. Normalization of T levels in men with MS improved obesity, glycemic control, blood pressure, lipid profile, and bone mineral density compared with controls. Amelioration in hormonal parameters, that is, vitamin D, growth hormone, and thyrotropin plasma levels, were reported.
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http://dx.doi.org/10.1155/2014/527470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945028PMC
April 2014

Trunk fat negatively influences skeletal and testicular functions in obese men: clinical implications for the aging male.

Int J Endocrinol 2013 20;2013:182753. Epub 2013 Nov 20.

Department of Experimental Medicine, Medical Pathophysiology, Food and Science and Endocrinology Section, "Sapienza" University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.

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, 17 β -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 (r (2) = -0.26, P < 0.01) and between HOMA-IR and OSCA levels (r (2) = -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, r (2) = -0.20; P < 0.001, r (2) = -0.24) was found, independently from age. An inverse correlation between E2 levels, BMDL, and BMDH (P < 0.001, r (2) = -0.20; P < 0.001, r (2) = -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.
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http://dx.doi.org/10.1155/2013/182753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854658PMC
December 2013

Effects of 5-year treatment with testosterone undecanoate on lower urinary tract symptoms in obese men with hypogonadism and metabolic syndrome.

Urology 2014 Jan 16;83(1):167-73. Epub 2013 Oct 16.

Experimental Medicine Department, Endocrinology and Food and Science Section, "Sapienza" University of Rome, Rome, Italy. Electronic address:

Objective: To investigate the possible effects of testosterone undecanoate (TU) injections in a population of obese (mean age 57) hypogonadal men with lower urinary tract symptoms (LUTS) in a long-term observational study.

Methods: Twenty obese hypogonadal men with metabolic syndrome were treated with TU injections every 12 weeks for 60 months; also 20 matched subjects in whom TU was unaccepted or contraindicated were used as controls. LUTS severity and the impact of TU injections were assessed by differences in International Prostate Symptom Score (IPSS), maximum urinary flow (Qmax) rate in milliliters, post-void residual (PVR) volume, and prostate size every 12 months in a 5-year controlled study.

Results: TU injections did not produce differences in IPSS, Qmax, PVR, and prostate size in both groups. No modification in prostate-specific antigen (PSA) and hematocrit levels was also found between the 2 groups. Interestingly, controls showed increased incidence of prostatitis than TU-treated men (10% vs 30%, P <.01).

Conclusion: We showed that 5 years of TU treatment did not change IPSS, PVR, Qmax, or prostate size in obese hypogonadal men with metabolic syndrome and moderate LUTS at baseline. Therefore, long-term TU replacement therapy is a safe and effective treatment for reverting hypogonadal features related to metabolic syndrome and does not impact negatively on LUTS and prostate volume.
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http://dx.doi.org/10.1016/j.urology.2013.08.019DOI Listing
January 2014

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

J Sex Med 2013 Oct 11;10(10):2373-81. Epub 2013 Jul 11.

Department of Experimental Medicine, Endocrinology and Food and Science Section, Sapienza University of Rome, Rome, Italy.

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.

Aim: To 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.

Methods: A 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 Measures: Clinical 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.
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http://dx.doi.org/10.1111/jsm.12268DOI Listing
October 2013

An update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors.

Expert Opin Pharmacother 2013 Jul 16;14(10):1333-44. Epub 2013 May 16.

Sapienza University of Rome, Endocrinology and Food and Science Section, Rome, Italy.

Introduction: Phosphodiesterase type 5 inhibitors (PDE5-i) are used for the oral treatment of erectile dysfunction (ED). Since the launch of sildenafil more than 15 years ago, new molecules have become available. At present, in addition to tadalafil and vardenafil, there are three other drugs, udenafil, avanafil and mirodenafil, marketed in some countries which appear to be promising.

Areas Covered: The clinical pharmacological differences in dosage and side effects of all PDE5-i are evaluated.

Expert Opinion: All PDE5-i are equally effective and safe for the treatment of ED. On-demand use of any PDE5-i is also safe for patients with comorbid conditions. Tadalafil seems to be the preferred drug by patients and physicians, probably due to its peculiar pharmacological profile that makes sexual intercourse more spontaneous for the patients. Preliminary data suggest that the use of vardenafil may also be beneficial in cases of ED associated with premature ejaculation. Daily treatment is another option in men with ED and documented vascular or prostate disease. In geriatric or in difficult-to-treat populations, the evaluation of testosterone plasma levels will help to predict the efficacy of any PDE5-i. Remarkably, when such drugs are withdrawn for any reason, ED most often continues to occur because of the presence of an underlying disease.
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http://dx.doi.org/10.1517/14656566.2013.799665DOI Listing
July 2013

Peripheral arterial tonometry to measure the effects of vardenafil on sympathetic tone in men with lifelong premature ejaculation.

Int J Endocrinol 2013 27;2013:394934. Epub 2013 Mar 27.

Department of Experimental Medicine, Section of Medical Pathophysiology, viale Regina Elena 324, Sapienza University of Rome, 00161 Rome, Italy.

To elucidate whether adrenergic overtone is involved in the pathophysiology of men with lifelong (LL) premature ejaculation (PE), we investigated differences in reactive hyperemia index (RHI) responses by using peripheral arterial tonometry (PAT). 20 men with LL-PE (18-40 years) were enrolled in an 8-week, double-blind, placebo-controlled, crossover study and compared with 10 age-matched controls without LL-PE. Primary endpoints were PAT modifications induced by vardenafil 10 mg on demand. Secondary endpoints were the improvement in intravaginal ejaculatory latency time (IELT) as measured by the stopwatch technique and variations in anxiety scores at Stai-X1 for state-anxiety and Stai-X2 for trait-anxiety. At baseline, men with LL-PE showed higher RHI variation (P < 0.001), Stai-X1 and Stai X2 scores (P < 0.0001, resp.), and prolactin levels (P < 0.05) compared with controls. Vardenafil treatment markedly reduced RHI variation in men with LL-PE (P < 0.01) when compared with placebo. Mean changes in geometric IELT were higher after taking vardenafil (0.6 ± 0.3 versus 4.5 ± 1.1 min, P < 0.01) when compared with placebo. STAI-X1 and STAI-X2 scores fell within the normal range after treatment with vardenafil (P < 0.01). Vardenafil was an effective treatment in men with LL-PE; improvements of IELT may be due to increased NO production which is able to reduce adrenergic overactivity and anxiety levels.
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http://dx.doi.org/10.1155/2013/394934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623392PMC
April 2013

Negative association between trunk fat, insulin resistance and skeleton in obese women.

World J Diabetes 2013 Apr;4(2):31-9

Emanuela A Greco, Davide Francomano, Rachele Fornari, Chiara Marocco, Carla Lubrano, Lorenzo M Donini, Andrea Lenzi, Antonio Avers, Silvia Migliaccio, Department of Experimental Medicine, Section of Medical Pathophysiology, Endocrinology and Nutrition, University "Sapienza" of Rome, 00195 Rome, Italy.

Aim: To evaluate the potential interference of trunk fat (TF) mass on metabolic and skeletal metabolism.

Methods: In this cross-sectional study, 340 obese women (mean age: 44.8 ± 14 years; body mass index: 36.0 ± 5.9 kg/m(2)) were included. Patients were evaluated for serum vitamin D, osteocalcin (OSCA), inflammatory markers, lipids, glucose and insulin (homeostasis model assessment of insulin resistance, HOMA-IR) levels, and hormones profile. Moreover, all patients underwent measurements of bone mineral density (BMD; at lumbar and hip site) and body composition (lean mass, total and trunk fat mass) by dual-energy X-ray absorptiometry.

Results: Data showed that: (1) high TF mass was inversely correlated with low BMD both at lumbar (P < 0.001) and hip (P < 0.01) sites and with serum vitamin D (P < 0.0005), OSCA (P < 0.0001) and insulin-like growth factor-1 (IGF-1; P < 0.0001) levels; (2) a positive correlation was found between TF and HOMA-IR (P < 0.01), fibrinogen (P < 0.0001) and erythrocyte sedimentation rate (P < 0.0001); (3) vitamin D levels were directly correlated with IGF-1 (P < 0.0005), lumbar (P < 0.006) and hip (P < 0.01) BMD; and (4) inversely with HOMA-IR (P < 0.001) and fibrinogen (P < 0.0005).Multivariate analysis demonstrated that only vitamin D was independent of TF variable.

Conclusion: In obese women, TF negatively correlates with BMD independently from vitamin D levels. Reduced IGF-1 and increased inflammatory markers might be some important determinants that account for this relationship.
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http://dx.doi.org/10.4239/wjd.v4.i2.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627415PMC
April 2013

Weight loss by multidisciplinary intervention improves endothelial and sexual function in obese fertile women.

J Sex Med 2013 Apr 24;10(4):1024-33. Epub 2013 Jan 24.

Department of Experimental Medicine, Medical Physiopathology, Food Science and Endocrinology Section, Viale Policlinico 155,Rome, Italy.

Introduction: Weight loss in sexually active women improves their quality of life. At present, no studies have investigated whether weight loss may affect female sexual function in severe obese women.

Aim: The aim of this study was to investigate the effects of different programs of weight loss on female sexual dysfunction complaints and on endothelial function in premenopausal obese females.

Methods: Forty-four out of overall 80 obese fertile women (age 18-49 years; mean 36 years) were enrolled because of sexual complaints at Female Sexual Function Index-6 (FSFI-6 score ≤19). Patients were then allocated to different treatments of 8 weeks duration each: an intensive residential program with hypocaloric diet plus controlled physical exercise along with lifestyle modifications at a specialized clinic (Group A, N = 23) and a non-intensive outpatient clinic program consisting of hypocaloric diet and physical exercise at home (Group B, N = 21). Afterward, overall patients were allocated to an extended 8-week follow-up period consisting of outpatient clinic controlled diet plus physical exercise at home.

Main Outcome Measures: Primary end points were modifications of FSFI-6 scores and endothelial function as measured by reactive hyperemia (RHI) with EndoPat-2000. Secondary end points were modifications in body composition as measured by dual-energy X-ray absorptiometry (DEXA).

Results: After 16 weeks, FSFI-6 score and the frequency of sexual activity were significantly higher in Group A compared with Group B (P < 0.01), and significant improvements in arousal, lubrication, and satisfaction sub-domain scores were also found (P < 0.01). Group A showed improvements in RHI (P < 0.01) and marked improvement in homeostasis model assessment of insulin resistance (P < 0.001), anthropometric parameters as weight (P < 0.01), body mass index (P < 0.01), fat mass (P < 0.0001), and percentage of fat mass (P < 0.005) compared with Group B. A relationship between peak insulin (P < 0.0001) and RHI (P < 0.001) vs. FSFI-6 scores was found, respectively.

Conclusions: A multidisciplinary approach to female obesity appears to be superior to conventional outpatient clinic to produce weight loss and to improve several aspects of sexual dysfunction in obese women. Such changes might be related to persistent improvements in endothelial function and in insulin resistance.
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http://dx.doi.org/10.1111/jsm.12069DOI Listing
April 2013

Cardiometabolic complications after androgen deprivation therapy in a man with prostate cancer: effects of 3 years intermittent testosterone supplementation.

Front Endocrinol (Lausanne) 2012 16;3:17. Epub 2012 Feb 16.

Department of Experimental Medicine, Medical Physiopathology, Food Science and Endocrinology Section, Sapienza University of Rome Rome, Italy.

Androgen deprivation therapy (ADT) for prostate carcinoma (PCa) may cause cardiometabolic complications unless intermittent androgen blockade (IAB) is instituted. An 80-year-old caucasian man was diagnosed intermediate grade (Gleason 4 + 3) PCa and was treated with continuous ADT with triptorelin plus bicalutamide. After 6 months of treatment, he experienced an acute myocardial infarction and 1 month after hospitalization he came to our outpatient clinic for fatigue, weight gain, and hyperglycemia. Due to iatrogenic hypogonadism, we decided to proceed with IAB, but after 3 months ADT withdrawal his serum testosterone (T) was still 0.5 ng/mL. Due to very low concomitant PSA levels (0.1 ng/mL) he was then proposed intermittent T-gel supplementation (Tostrex(®)) which was initiated according to the following scheme: 6 months on and 3 months off. T-gel dose was titrated tri-weekly in order to achieve T plasma levels below 3.49 ng/mL. After 6 months on, his serum T raised to a mean value of about 2.0 ng/mL without increments in PSA. After overall 12 months on, his serum T peaked to a mean value of 3.0 ng/mL while a delay in PSA rise was seen after 24 months (0.6 ng/mL) but remained stable until the last observation carried forward (LOCF), at 45 months. No clinical and biochemical PCa progression were observed at LOCF. Reversion of iatrogenic metabolic syndrome started after 6 months of T supplementation without using any add-on treatment. This case provides support that once regression of PCa growth is attained, T supplementation may be administered in well differentiated PCa, especially if IAB is not successful in reverting iatrogenic hypogonadism and its associated cardiac and metabolic complications.
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http://dx.doi.org/10.3389/fendo.2012.00017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3355839PMC
August 2012

Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study.

Aging Male 2012 Jun 23;15(2):96-102. Epub 2012 Mar 23.

Department of Experimental Medicine, Medical Pathophysiology, Food and Science and Endocrinology Section, Sapienza University of Rome, Rome, Italy.

We evaluated the effects of long-term testosterone replacement therapy (TRT) on the bone mineral density (BMD) in obese patients with metabolic syndrome (MS) and late-onset hypogonadism (LOH). Sixty men (mean age 57 ± 10) with low serum testosterone (T < 320 ng/dL) and MS regardless the presence of osteoporosis were enrolled. Forty men received intramuscular T-undecanoate (TU) four times/year for 36 months and 20 age-matched hypogonadal men with MS in whom T treatment was contraindicated were used as controls. Hormonal, biochemical markers, vertebral and femoral BMD by dual-energy x-ray absorptiometry were measured. At baseline, overall patients had mild osteopenia (lumbar BMD= 0.891 ± 0.097 g/cm(2); femoral BMD= 0.847 ± 0.117 g/cm(2)). TU induced a significant improvement of bone mass after 36 months (lumbar BMD=1.053 ± 0.145 g/cm(2); p < 0.002; femoral BMD=0.989 ± 0.109; p < 0.003 g/cm(2)) with a 5%/year increase and a significant reduction in hs-CRP without changes in body mass index. A direct relationship between serum T and BMD increments at the lumbar (r(2) = 0.66, p < 0.0001) and femoral (r(2) =0.52, p < 0.0001) sites was demonstrated. Study adherence was 50% without serious side effects. Long-term TRT in middle-aged men with LOH and MS determines a significant increase in both vertebral and femoral BMD related to increased serum T levels, probably independently from estradiol modifications.
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http://dx.doi.org/10.3109/13685538.2011.631230DOI Listing
June 2012

A spontaneous, double-blind, double-dummy cross-over study on the effects of daily vardenafil on arterial stiffness in patients with vasculogenic erectile dysfunction.

Int J Cardiol 2012 Oct 5;160(3):187-91. Epub 2011 May 5.

Department of Experimental Medicine-Medical Pathophysiology, Food Science and Endocrinology Section, University “Sapienza”, Rome, Italy.

Background: It is known that the incidence of endothelial dysfunction in patients with vascular erectile dysfunction (ED) is increased. The effects of daily vardenafil on endothelial function and arterial stiffness in patients with erectile dysfunction (ED) have never been investigated.

Methods: 20 men complaining vascular ED (mean IIEF5=12 ± 6 and peak systolic velocity-PSV=24 ± 2 cm/s) were enrolled in a 4-week, randomized, double-blind, double-dummy, crossover study (mean age 59 ± 11) and received either vardenafil 10mg daily or 20mg on-demand with a two-week washout interval. Primary endpoints were variation from baseline of reactive hyperemia (RH) and augmentation index (AI) calculated by fingertip peripheral arterial tonometry (PAT) device. Secondary endpoints were variations of IIEF-5 and SEP3 scores from baseline and plasma surrogate markers of endothelial function, i.e. endothelin-1 (ET-1) and adrenomedullin (ADM).

Results: Patients who took daily vardenafil (vs. on-demand) reported significant (P<0.01) improvements in arterial stiffness as evaluated by AI and reduction of plasma ADM levels (p<0.05) but no improvement in average RH. When corrected for heart rate, ADM showed a strong direct relationship with AI (r(2)=0.22; p<0.005). The proportion of patients with an IIEF5 score of ≥ 22 or in SEP3 percentage of success rates were similar. Each treatment resulted in significantly greater IIEF5 scores (p<0.001) and better SEP3 response rates (p<0.0001) compared with baseline.

Conclusions: We demonstrated that daily vardenafil improves arterial stiffness and erectile function measurements in men with severe vasculogenic ED. This effect may be mediated, at least in part, by a reduction in ADM circulating levels.
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http://dx.doi.org/10.1016/j.ijcard.2011.04.003DOI Listing
October 2012

Exposure to phosphodiesterase type 5 inhibitors stimulates aromatase expression in human adipocytes in vitro.

J Sex Med 2011 Mar 22;8(3):696-704. Epub 2010 Dec 22.

Department of Experimental Medicine, Section of Medical Pathophysiology-Sapienza University of Rome, Rome, Italy.

Introduction: Prolonged tadalafil administration in men with erectile dysfunction is associated with increased testosterone (T): estradiol (E(2)) ratio mainly related to reduction of E(2) levels.

Aim: To investigate the presence of phosphodiesterase type 5 (PDE5) isoenzyme in primary human visceral adipocytes and whether different PDE5 inhibitors (PDE5i) could directly modulate aromatase (ARO) expression in differentiated human visceral adipocytes in culture.

Main Outcome Measures: PDE5 mRNA and protein expression in primary human visceral adipocytes as well as mRNA and protein expression of ARO, with functional activity after selective PDE5 blockade by tadalafil and sildenafil.

Methods: Purified primary human visceral pre-adipocytes were differentiated ex vivo and were exposed to tadalafil or sildenafil (1 µM) for different intervals of time (6-12-24-96 hours). ARO mRNA content and expression were measured by Western Blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively. T and E(2) in supernatants were measured by ELISA also in the presence of letrozole.

Results: Differentiated adipocytes were found to express detectable levels of PDE5 transcripts. Acute exposure (6 hours) to both PDE5i tadalafil and sildenafil increased ARO mRNA expression by 4.7- and 2.8-fold, respectively (P < 0.001). ARO mRNA and protein levels were increased by the treatment with PDE5i in a time- and dose-dependent manner. Such effect was mimicked by 8-bromo-cGMP but was lost after 24 and 96 hours; differently, the PDE3B specific inhibitor milrinone (1 µM), displayed no effect. Accordingly, long-term exposure (24 and 96 hours) to PDE5i caused a significant increase in E(2) concentrations in the supernatant (1.7 and 2 fold, respectively; P < 0.001), with a parallel reduction of T (15% and 30%, respectively; P < 0.001). Such effect was reversed by the co-incubation with the specific ARO-inhibitor letrozole.

Conclusions: Our results demonstrate that PDE5 is expressed in human visceral adipocytes and that acute exposure to PDE5i selectively stimulates ARO expression, which is related to a specific PDE5 blockade. We speculate that modulation of ARO activity by PDE5i could be one of the mechanisms responsible, at least in part, for the beneficial effects of PDE5i on endothelial and metabolic functions.
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http://dx.doi.org/10.1111/j.1743-6109.2010.02152.xDOI Listing
March 2011

Penile involvement in Systemic Sclerosis: New Diagnostic and Therapeutic Aspects.

Int J Rheumatol 2010 5;2010:708067. Epub 2010 Oct 5.

Department of Experimental Medicine, Internal Medicine Unit, Università degli Studi di Roma 'La Sapienza', 00161 Rome, Italy.

Systemic Sclerosis (SSc) is a connective tissue disorder featuring vascular alterations and an immunological activation leading to a progressive and widespread fibrosis of several organs such as the skin, lung, gastrointestinal tract, heart, and kidney. Men with SSc are at increased risk of developing erectile dysfunction (ED) because of the evolution of early microvascular tissutal damage into corporeal fibrosis. The entity of penile vascular damage in SSc patients has been demonstrated by using Duplex ultrasonography and functional infra-red imaging and it is now clear that this is a true clinical entity invariably occurring irrespective of age and disease duration and constituting the ''sclerodermic penis". Once-daily phosphodiesterase type-5 (PDE5) inhibitors improve both sexual function and vascular measures of cavernous arteries by improving surrogate markers of endothelial dysfunction, that is, plasma endothelin-1 and adrenomedullin levels, which may play a potential role in preventing progression of penile fibrosis and ED. Also, the beneficial effect of long-term PDE5i add-on therapy to SSc therapy in the treatment of Raynaud's phenomenon is described.
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http://dx.doi.org/10.1155/2010/708067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958513PMC
July 2011

Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study.

J Sex Med 2010 Oct;7(10):3495-503

Department of Medical Pathophysiology, Sapienza University of Rome, Italy.

Introduction: Longitudinal studies have demonstrated that male hypogonadism could be considered a surrogate marker of incident cardiovascular disease.

Aim: To evaluate the effects of parenteral testosterone undecanoate (TU) in outclinic patients with metabolic syndrome (MS) and late-onset hypogonadism (total testosterone (T) at or below 11nmol/L or free T at or below 250pmol/L).

Methods: This is a randomized, double-blind, double-dummy, placebo-controlled, parallel group, single-center study. Fifty patients (mean age 57±8) were randomized (4:1) to receive TU 1,000mg (every 12 weeks) or placebo (PLB) gel (3-6 g/daily) for 24 months.

Main Outcome Measures: Homeostasis model assessment index of insulin resistance (HOMA-IR), carotid intima media thickness (CIMT), and high-sensitivity C-reactive protein (hsCRP).

Results: At baseline, all patients fulfilled the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) and International Diabetes Federation (IDF) criteria for the definition of MS. An interim analysis conducted at 12 months showed that TU markedly improved HOMA-IR (P < 0.001), CIMT (P < 0.0001), and hsCRP (P<0.001) compared with PLB; thus, all patients were shifted to TU treatment. After 24 months, 35% (P < 0.0001) and 58% (P < 0.001) of patients still presented MS as defined by NCEP-ATPIII and IDF criteria, respectively. Main determinants of changes were reduction in waist circumference (P<0.0001), visceral fat mass (P<0.0001), and improvement in HOMA-IR without changes in body mass index (BMI).

Conclusions: TU reduced fasting glucose, waist circumference, and improved surrogate markers of atherosclerosis in hypogonadal men with MS. Resumption and maintenance of T levels in the normal range of young adults determines a remarkable reduction in cardiovascular risk factors clustered in MS without significant hematological and prostate adverse events.
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http://dx.doi.org/10.1111/j.1743-6109.2010.01931.xDOI Listing
October 2010

Cardiovascular effect of testosterone replacement therapy in aging male.

Acta Biomed 2010 ;81 Suppl 1:101-6

Department of Medical Pathophysiology, Sapienza University of Rome.

Cardiovascular diseases (CVD) are the most important causes of morbidity and mortality in the developed and developing world. Particularly, coronary heart disease is the commonest cause of death worldwide. Testosterone (T) is an anabolic hormone with putative beneficial effects on men's health and restoration of normal T levels in deficient men represents an important key-point of male well-being. In the lasts years it has emerged a possible linkage between androgen deficiency and CVD. Many studies noted that T deficiency might contribute to increased risk of CVD. Furthermore, androgen deficiency is frequently associated with increased levels of glucose, total cholesterol, low-density lipoprotein, increased production of pro-inflammatory cytokines, and increased thickness of the arterial wall that all contribute to worsen endothelial function. The clinical and epidemiological studies discussed in this section give an update on the interplay between late onset hypogonadism (LOH) and CVD. The linkage between androgen deficiency and men's vascular health has a great impact in the modern approach to the ageing male, and should be further investigated to determine the therapeutic potential of androgens in men with vascular disease.
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July 2010

Endothelial dysfunction and erectile dysfunction in the aging man.

Int J Urol 2010 Jan 25;17(1):38-47. Epub 2009 Nov 25.

Department of Medical Pathophysiology, Sapienza University of Rome, Rome, Italy.

Penile erection is a vascular event that requires an intact endothelium to occur. A dysfunctional endothelium is an early marker for the development of atherosclerotic changes and can also contribute to the occurrence of acute cardiovascular events. The pathogenesis of both endothelial and erectile dysfunction (ED) is intimately linked through decreased expression and activation of endothelial nitric oxide (NO) synthase, and the subsequent blunted physiological actions of NO naturally occurring with aging. It is now well-understood that ED is a symptom of underlying disease rather than a disease itself; for this reason in the near future both general practitioners, internal medicine practitioners and many specialists will have to interplay with sexual medicine. Aging in the man is also associated with several changes in arterial structure and function, part of them related to the decline of circulating levels of steroids, that is, testosterone and estradiol. These changes may be responsible, in part, for the lack of efficacy of ED treatments. The recent discovery that chronic administration of phosphodiesterase type 5 inhibitors may improve erectile and endothelial responsiveness of men previously non-responsive to on-demand regimes, and the knowledge that testosterone is one of the main modulators of the expression of penile phosphodiesterase type 5 isoenzyme, opens a new scenario in the treatment of men with ED and co-morbidities. The aim of this review is to discuss the pathophysiology of endothelial dysfunction and its relationship with ED in the aging male, and to suggest possible strategies to improve arterial function with regard to sexual dysfunctions.
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http://dx.doi.org/10.1111/j.1442-2042.2009.02426.xDOI Listing
January 2010

Testosterone and phosphodiesterase type-5 inhibitors: new strategy for preventing endothelial damage in internal and sexual medicine?

Ther Adv Urol 2009 Oct;1(4):179-97

Dip.to Fisiopatologia Medica, Room 37, Viale Policlinico 155, 00161 Rome Italy.

Normal vascular endothelium is essential for the synthesis and release of substances affecting vascular tone (e.g. nitric oxide; NO), cell adhesion (e.g. endothelins, interleukins), and the homeostasis of clotting and fibrinolysis (e.g. plasminogen inhibitors, von Willebrand factor). The degeneration of endothelial integrity promotes adverse events (AEs) leading to increased atherogenesis and to the development of vascular systemic and penile end-organ disease. Testosterone (T) is an important player in the regulation of vascular tone through non-genomic actions exerted via blockade of extracellular-calcium entry or activation of potassium channels; also, adequate T concentrations are paramount for the regulation of phosphodiesterase type-5 (PDE5) expression and finally, for the actions exerted by hydrogen sulphide, a gas involved in the alternative pathway controlling vasodilator responses in penile tissue. It is known that an age-related decline of serum T is reported in approximately 20 to 30% of men whereas T deficiency is reported in up to 50% of men with metabolic syndrome or diabetes. A number of laboratory and human studies have shown the combination of T and other treatments for erectile dysfunction (ED), such as PDE5 inhibitors, to be more beneficial in patients with ED and hypogonadism, who fail monotherapy for sexual disturbances.The aim of this review is to show evidence on the role of T and PDE5 inhibitors, alone or in combination, as potential boosters of endothelial function in internal medicine diseases associated with reduced T or NO bioavailability, i.e. metabolic syndrome, obesity, diabetes, coronary artery disease, hyperhomocysteinemia, that share common risk factors with ED. Furthermore, the possibility of such a strategy to prevent endothelial dysfunction in men at increased cardiovascular risk is discussed.
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http://dx.doi.org/10.1177/1756287209344992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126062PMC
October 2009

Redefining the role of long-acting phosphodiesterase inhibitor tadalafil in the treatment of diabetic erectile dysfunction.

Curr Diabetes Rev 2008 Feb;4(1):24-30

Dept. Medical Pathophysiology, Sapienza University of Rome, Italy.

Diabetes mellitus (DM) is an established risk factor predisposing to male erectile dysfunction (ED), and it has been calculated that more than 50% of diabetic men develop ED within ten years of diagnosis. It has been suggested that the risk of ED increases with metabolic indices of inadequate diabetes control and with a longer duration of disease. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the pathogenesis of diabetic ED. Coronary and peripheral atherosclerosis are frequent complications of DM and diabetic patients have an increased risk of future cardiovascular events comparable to that of patients with coronary artery disease. The prolonged half-life of tadalafil (17.5 hours) and its prolonged period of responsiveness (36-hours), constitute an ideal pharmacokinetic profile for once-a-day dosing and makes it an ideal candidate for rehabilitative therapy in DM patients, whereas a poor compliance with on-demand schedule is reported. The aim of this review will be to give an update on clinical overall efficacy and safety of tadalafil trials, i.e in diabetic population, and finally provide evidences for redefining the role of chronic treatment in selected group of patients.
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http://dx.doi.org/10.2174/157339908783502389DOI Listing
February 2008

Chronic sildenafil in men with diabetes and erectile dysfunction.

Expert Opin Drug Metab Toxicol 2007 Jun;3(3):451-64

University of Rome La Sapienza, Dept of Medical Pathophysiology, Viale Policlinico 155 - 00161 Rome, Italy.

Erectile dysfunction frequently represents a neurovascular complication of diabetes mellitus, and it has been calculated that almost 50% of diabetic men will have erectile dysfunction within 6 years after diagnosis. Penile endothelial and smooth muscle cell dysfunction are due to molecular pathway abnormalities (i.e., activation of PKC, increased oxidative stress and overproduction of advanced-glycosylation end products). The response rate to oral drug therapies, such as sildenafil, is lower than in most other groups. Because therapeutic alternatives (i.e., intracavernous injections with vasoactive agents) are not curative, clinical trials aimed to demonstrate rehabilitative effects with daily phosphodiesterase type-5 inhibitors are ongoing. If this approach proves successful, it will determine many advantages over the intracavernosal treatment and potentially induce sexual rehabilitation.
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http://dx.doi.org/10.1517/17425255.3.3.451DOI Listing
June 2007
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