Publications by authors named "Giovanni Spera"

50 Publications

Baseline HOMA IR and Circulating FGF21 Levels Predict NAFLD Improvement in Patients Undergoing a Low Carbohydrate Dietary Intervention for Weight Loss: A Prospective Observational Pilot Study.

Nutrients 2020 Jul 18;12(7). Epub 2020 Jul 18.

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

Background: Non-alcoholic fatty liver disease (NAFLD) is a major cause of liver disease. Very low-calorie ketogenic diets (VLCKD) represent a feasible treatment as they induce profound weight loss and insulin resistance (IR) improvement. Despite the recognized benefits on NAFLD deriving from pharmacological administration of fibroblast growth factor 21 (FGF21), whose endogenous counterpart is a marker of liver injury, little is known about its physiology in humans.

Aim: To identify predictors of NAFLD improvement as reflected by the reduction of the non-invasive screening tool hepatic steatosis index (HSI) in obese patients undergoing a weight loss program.

Methods: Sixty-five obese patients underwent a 90-day dietary program consisting of a VLCKD followed by a hypocaloric low carbohydrate diet (LCD). Anthropometric parameters, body composition, and blood and urine chemistry were assessed.

Results: Unlike most parameters improving mainly during the VLCKD, the deepest HSI change was observed after the LCD ( = 0.02 and < 0.0001, respectively). Baseline HOMA-IR and serum FGF21 were found to be positive (R = 0.414, = 0009) and negative (R = 0.364, = 0.04) independent predictors of HSI reduction, respectively.

Conclusions: We suggest that patients with IR and NAFLD derive greater benefit from a VLCKD, and we propose a possible role of human FGF21 in mediating NAFLD amelioration following nutritional manipulation.
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http://dx.doi.org/10.3390/nu12072141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400878PMC
July 2020

Very-Low-Calorie Ketogenic Diets With Whey, Vegetable, or Animal Protein in Patients With Obesity: A Randomized Pilot Study.

J Clin Endocrinol Metab 2020 09;105(9)

Department of Experimental Medicine, University of Rome "La Sapienza," Rome, Italy.

Context: We compared the efficacy, safety, and effect of 45-day isocaloric very-low-calorie ketogenic diets (VLCKDs) incorporating whey, vegetable, or animal protein on the microbiota in patients with obesity and insulin resistance to test the hypothesis that protein source may modulate the response to VLCKD interventions.

Subjects And Methods: Forty-eight patients with obesity (19 males and 29 females, homeostatic model assessment (HOMA) index ≥ 2.5, aged 56.2 ± 6.1 years, body mass index [BMI] 35.9 ± 4.1 kg/m2) were randomly assigned to three 45-day isocaloric VLCKD regimens (≤800 kcal/day) containing whey, plant, or animal protein. Anthropometric indexes; blood and urine chemistry, including parameters of kidney, liver, glucose, and lipid metabolism; body composition; muscle strength; and taxonomic composition of the gut microbiome were assessed. Adverse events were also recorded.

Results: Body weight, BMI, blood pressure, waist circumference, HOMA index, insulin, and total and low-density lipoprotein cholesterol decreased in all patients. Patients who consumed whey protein had a more pronounced improvement in muscle strength. The markers of renal function worsened slightly in the animal protein group. A decrease in the relative abundance of Firmicutes and an increase in Bacteroidetes were observed after the consumption of VLCKDs. This pattern was less pronounced in patients consuming animal protein.

Conclusions: VLCKDs led to significant weight loss and a striking improvement in metabolic parameters over a 45-day period. VLCKDs based on whey or vegetable protein have a safer profile and result in a healthier microbiota composition than those containing animal proteins. VLCKDs incorporating whey protein are more effective in maintaining muscle performance.
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http://dx.doi.org/10.1210/clinem/dgaa336DOI Listing
September 2020

Beneficial effects of the ketogenic diet on nonalcoholic fatty liver disease: A comprehensive review of the literature.

Obes Rev 2020 08 24;21(8):e13024. Epub 2020 Mar 24.

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

Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease, characterized by hepatic fat accumulation and possible development of inflammation, fibrosis, and cancer. The ketogenic diet (KD), with its drastic carbohydrate reduction, is a now popular weight loss intervention, despite safety concerns on a possible association with fatty liver. However, KDs were also reported to be beneficial on hepatic pathology, with ketone bodies recently proposed as effective modulators of inflammation and fibrosis. If the beneficial impact of weight loss on NAFLD is established, less is known on the effect of macronutrient distribution on such outcome. In a hypocaloric regimen, the latter seems not to be crucial, whereas at higher calorie intake, macronutrient ratio and, theoretically, ketosis, may become important. KDs could positively impact NAFLD for their very low carbohydrate content, and whether ketosis plays an additional role is unknown. Indeed, several mechanisms may directly link ketosis and NAFLD improvement, and elucidating these aspects would pave the way for new therapeutic strategies. We herein aimed at providing an accurate revision of current literature on KDs and NAFLD, focusing on clinical evidence, metabolic pathways involved, and strict categorization of dietary interventions.
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http://dx.doi.org/10.1111/obr.13024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379247PMC
August 2020

Very Low-Calorie Ketogenic Diet: A Safe and Effective Tool for Weight Loss in Patients With Obesity and Mild Kidney Failure.

Nutrients 2020 Jan 27;12(2). Epub 2020 Jan 27.

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

Very low-calorie ketogenic diets (VLCKD) are an effective and increasingly used tool for weight loss. Traditionally considered high protein, ketogenic diets are often looked at with concern by clinicians due to the potential harm they pose to kidney function. We herein evaluated the efficacy and safety of a VLCKD in patients with obesity and mild kidney failure. A prospective observational real-life study was conducted on ninety-two patients following a VLCKD for approximately 3 months. Thirty-eight had mild kidney failure and fifty-four had no renal condition and were therefore designated as control. Anthropometric parameters, bioelectrical impedance and biochemistry data were collected before and at the end of the dietary intervention. The average weight loss was nearly 20% of initial weight, with a significant reduction in fat mass. We report an improvement of metabolic parameters and no clinically relevant variation regarding liver and kidney function. Upon stratification based on kidney function, no differences in the efficacy and safety outcomes were found. Interestingly, 27.7% of patients with mild renal failure reported normalization of glomerular filtrate after dietary intervention. We conclude that, when conducted under the supervision of healthcare professionals, a VLCKD is an effective and safe treatment for weight loss in patients with obesity, including those affected by mild kidney failure.
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http://dx.doi.org/10.3390/nu12020333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071259PMC
January 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

Safety and efficacy of a multiphase dietetic protocol with meal replacements including a step with very low calorie diet.

Endocrine 2015 Apr 26;48(3):863-70. Epub 2014 Jul 26.

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

To investigate safety, compliance, and efficacy, on weight loss and cardiovascular risk factors of a multiphasic dietary intervention based on meal replacements, including a period of very low calorie diet (VLCD) in a population of obese patients. Anthropometric parameters, blood tests (including insulin), dual-energy-X-ray absorptiometry (DXA), and questionnaires for the assessment of safety and compliance before and after (phase I) a 30-day VLCD, 700 kcal/day, normoproteic, 50 g/day carbohydrate, four meal replacements; (phase II) a 30-day low calorie diet (LCD), 820 kcal/day, three meal replacements plus a protein plate; (phase III) 60-day LCD, 1,100 kcal/day, two meal replacements plus two protein plates and reintroduction of small amounts of carbohydrates; (phase IV) 60-day hypocaloric balanced diet (HBD), 1,200 kcal/day, one meal replacement, two protein plates and the reintroduction of carbohydrates. 24 patients (17 females, 7 males, mean BMI 33.8±3.2 kg/m2, mean age 35.1±10.2 years) completed the study. The average weight loss was 15.4±6.7%, with a significant reduction of fat mass (from 32.8±4.7 to 26.1±6.3% p<0.05) and a relative increase of lean mass (from 61.9±4.8 to 67.1±5.9% p<0.05). An improvement of metabolic parameters and no variations of the liver and kidney functions were found. A high safety profile and an excellent dietary compliance were seen. The VLCD dietary program and the replacement dietary system described here is an effective, safe, and well-tolerated treatment for weight control.
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http://dx.doi.org/10.1007/s12020-014-0355-2DOI Listing
April 2015

Obstructive sleep apnea and bone mineral density in obese patients.

Diabetes Metab Syndr Obes 2012 7;5:395-401. Epub 2012 Nov 7.

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

Context: Obesity and its co-morbidities may adversely affect bone mineral density (BMD). Obstructive sleep apnea (OSA) is a major complication of obesity. To date, the effects of OSA on BMD in obese patients have been poorly studied.

Objective: To examine whether the severity of OSA independently correlates with BMD in obese patients.

Methods: One hundred and fifteen obese subjects with OSA (Apnea/Hypopnea Index [AHI] ≥5 events per hour) were included in the study. BMD was measured at lumbar spine, total hip, and femoral neck by dual energy X-ray absorptiometry. Body mass index, lean mass, and representative measures of metabolic syndrome (waist circumference, fasting plasma glucose, blood pressure, HDL-cholesterol, triglycerides) and inflammation (ESR, CRP, fibrinogen) were also evaluated.

Results: BMD did not differ among obese individuals regardless of OSA severity. Correlation coefficient analysis for all the covariates showed a lack of association between AHI and BMD that was strongly influenced by age and weight.

Conclusion: Our study does not support an independent association between AHI and BMD in obese patients. Controlled studies involving a greater number of patients are warranted.
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http://dx.doi.org/10.2147/DMSO.S37761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496369PMC
November 2012

Erectile dysfunction of sclerodermic patients correlates with digital vascular damage.

Eur J Intern Med 2011 Jun 16;22(3):318-21. Epub 2010 Oct 16.

Sapienza University of Rome, Department of Clinical Medicine, Clinical Immunology Unit, Scleroderma Center, Italy.

Background: The prevalence of erectile dysfunction (ED) in men with systemic sclerosis (SSc) can be considered a manifestation of endothelium damage. Aim of the study is to investigate ED in SSc patients by color Doppler ultrasound examination and to correlate it with disease severity and digital vascular damage.

Methods: In 20 males SSc patients blood flow velocity in the cavernous artery was determined with Duplex ultrasonography. Naifold videocapillaroscopy, Sexual Health Inventory for Men (SHIM) and Medsger Disease Severity Scale (DSS) were performed. Arteriogenic ED was defined by the presence of a reduced peak systolic velocity (PSVs), while diastolic velocity (EDV) and the resistive index (RI) were estimated to evaluate venocclusive dysfunction. SSc patients are classified by capillaroscopic pattern and vascular domain of DSS into two groups: low vascular damage (early or active capillaroscopic pattern and score of vascular domain of DSS≤2) and high vascular damage (late capillaroscopic pattern and score of vascular domain of DSS≥3).

Results: In all SSc patients a reduction of SHIM is present (mean 13.5±6.3). Patients with less vascular damage have a significantly (p<0.001) higher score of SHIM than patients with greater vascular damage (19.2±2.4 vs 7.9±2.7). No significant difference (p>0.5) between the two groups of vascular damage was found in PSVs. Venocclusive dysfunction was present only (p<0.001) in the group with high vascular damage.

Conclusion: We can assert that there is a relationship between SSc vascular digital damage and ED.
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http://dx.doi.org/10.1016/j.ejim.2010.09.013DOI Listing
June 2011

Assessing disability in morbidly obese individuals: the Italian Society of Obesity test for obesity-related disabilities.

Disabil Rehabil 2011 4;33(25-26):2509-18. Epub 2011 May 4.

Department of Medical Physiopathology (Food Science Section)-Sapienza University of Rome, Italy.

Purpose: To validate a new obesity-specific disability assessment test: the Obesity-related Disability test (Test SIO Disabilità Obesità Correlata, TSD-OC).

Methods: Adult obese individuals were assessed with the TSD-OC, 36-Item Short-Form Health Survey (SF-36), 6-min walking test (6MWT) and grip strength. The TSD-OC is composed of 36 items divided into seven sections (pain, stiffness, activities of daily living and indoor mobility, housework, outdoor activities, occupational activities and social life). Statistical correlations between the TSD-OC, functional assessment (6MWT and grip strength) and quality of life parameters (SF-36) were analysed. Internal consistency was assessed with Cronbach's α test. Test-retest reliability was evaluated in a subgroup of 30 individuals. A linking exercise between TSD-OC items and categories of the International Classification of Functioning, Disability and Health was performed.

Results: Test-retest showed excellent stability (r = 0.90) and excellent internal consistency was reported (Cronbach's α > 0.90). Significant low to moderate correlations between TSD-OC, SF-36 scores, 6MWT and grip strength were observed. A total of 26 ICF categories were linked, mostly related to the area of mobility.

Conclusions: The TSD-OC is a reliable and valid instrument for measuring self-reported disability in obese subjects. It may represent an important tool for establishing rehabilitation needs in individuals with obesity-related disability, for planning appropriate rehabilitation programmes and for evaluating their effectiveness.
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http://dx.doi.org/10.3109/09638288.2011.575529DOI Listing
April 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

Severe oligozoospermia in a young man with chronic myeloid leukemia on long-term treatment with imatinib started before puberty.

Fertil Steril 2011 Mar;95(3):1120.e15-7

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Objective: To report the effect of long-term treatment with the tyrosine kinase inhibitor imatinib started before the onset of puberty on semen parameters, bone mineral density, and hormone values.

Design: Case report.

Setting: University hospital.

Patient(s): An 18-year-old man given treatment with imatinib for chronic myeloid leukemia.

Intervention(s): Clinical, biochemical and dual-energy X-ray absorptiometry evaluations.

Main Outcome Measure(s): Semen analysis, serum levels of gonadotropins, inhibin-B, and testosterone, bone mineral density, markers of skeletal homeostasis.

Result(s): Semen analyses showed severe oligozoospermia after long-term administration of imatinib started before puberty. The inhibin-B/FSH ratio was reduced. A low bone mineral density for chronologic age was observed.

Conclusion(s): This case study documents the potential risk of an impairment of semen parameters in patients undergoing a treatment with tyrosine kinase inhibitors before the complete maturation of the testis.
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http://dx.doi.org/10.1016/j.fertnstert.2010.08.060DOI Listing
March 2011

Role of platelet-derived growth factors in the testis.

Endocr Rev 2010 Dec 21;31(6):916-39. Epub 2010 Jul 21.

Department of Medical Physiopathology, I Faculty of Medicine, University of Rome La Sapienza, Policlinico Umberto I, 00161 Rome, Italy.

Normal development and function of the testis are controlled by endocrine and paracrine signaling pathways. Platelet-derived growth factors (PDGFs) are growth factors that mediate epithelial-mesenchymal interactions in various tissues during normal and abnormal processes such as embryo development, wound healing, tissue fibrosis, vascular disorders, and cancer. PDGFs and their receptors (PDGFRs) have emerged as key players in the regulation of embryonic and postnatal development of the male gonad. Cells that express PDGFs and PDGFRs are found in the testis of mammals, birds, and reptiles, and their distribution, regulation, and function vary across species. Testicular PDGFs and PDGFRs appear after the process of sex determination in animals that use either genetic sex determination or environmental sex determination. Sertoli cells are the main PDGF-producing cells during the entire period of prenatal and postnatal testis development. Fetal Leydig cells and their precursors, adult Leydig cells and their stem cell precursors, peritubular myoid cells, cells of the blood vessels, and gonocytes are the testicular cell types expressing PDGFRs. Genetically targeted deletions of PDGFs, PDGFRs, PDGFR target genes or pharmacological silencing of PDGF signaling produce profound damage on the target cells that, depending on the developmental period, are under direct or indirect control of PDGF. PDGF signaling may also serve diverse functions outside of the realm of testis development, including testicular tumors. In this review, we provide a framework of the current knowledge to clarify the useful information regarding how PDGFs function in individual cells of the testis.
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http://dx.doi.org/10.1210/er.2010-0004DOI Listing
December 2010

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

The ENDOTRIAL study: a spontaneous, open-label, randomized, multicenter, crossover study on the efficacy of sildenafil, tadalafil, and vardenafil in the treatment of erectile dysfunction.

J Sex Med 2009 Sep 29;6(9):2547-60. Epub 2009 Jun 29.

School of Sexology, Department of Experimental Medicine, University of L'Aquila, Coppito, L'Aquila, Italy.

Introduction: The three effective, commercially available drugs for the treatment of erectile dysfunction-sildenafil, vardenafil, and tadalafil-inhibit the same substrate, the erectolytic enzyme phosphodiesterase type 5 (PDE5). Although there are pharmacological differences between these three compounds, few comparative studies have been conducted to date.

Aim: The aim of this study was to determine the efficacy of sildenafil, tadalafil, and vardenafil in a randomly assigned 8-week fixed regimen.

Methods: This was a spontaneous, open-label, randomized, multicenter, crossover study where the patients were randomized to receive sildenafil 50 mg, sildenafil 100 mg, tadalafil 20 mg, or vardenafil 20 mg.

Main Outcome Measures: The primary outcome included the posttreatment analysis of erectile function domains of the abridged International Index of Erectile Function (IIEF5+1). The secondary objectives included the analysis of peak-systolic velocities (PSVs), end-diastolic velocities (EDVs), and resistive index (RI), and the estimate of the percentage of men with normal penile hemodynamic parameters after each treatment.

Results: In all groups of patients taking sildenafil 50 mg, sildenafil 100 mg, tadalafil 20 mg, and vardenafil 20 mg at a frequency reflecting the common treatment regimens in real life, there was a statistically significant baseline-to-end point improvement in subjective perception of erectile function measured by IIEF5+1. When the four groups were compared, the treatments were not different in modifying IIEF5+1 and penile flow parameters. However, the within-group analysis showed that PSV improved in the sildenafil 50 mg group and that PSV together with RI significantly ameliorated in patients receiving 100 mg of sildenafil. Regression analysis confirmed an independent effect of sildenafil on hemodynamic efficacy parameters.

Conclusions: An overall equivalence was demonstrated in the subjective perception of treatment benefits for all the PDE5i tested. However, sildenafil, in a dose-dependent manner, was the unique PDE5i able to ameliorate some of the penile flow parameters within the 8-week treatment period. These findings should be interpreted conservatively because of the observational nature of the study.
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http://dx.doi.org/10.1111/j.1743-6109.2009.01375.xDOI Listing
September 2009

Effects of chronic testosterone administration on myocardial ischemia, lipid metabolism and insulin resistance in elderly male diabetic patients with coronary artery disease.

Int J Cardiol 2010 Jun 9;142(1):50-5. Epub 2009 Apr 9.

Cardiovascular Research Unit Department of Medical Sciences, San Raffaele IRCCS-Rome, Italy.

Background: The evidence of antiatherogenic and vasodilatatory effects of testosterone (T) suggest a possible role of the lack of this hormone in the development and pathophysiology of coronary artery disease (CAD). Aim of the present study was to evaluate the effects of oral administration of testosterone undecanoate during a period of three months on serum lipid levels and on the occurrence of anginal attacks and daily ischemic episodes in patients with CAD.

Methods And Results: Eighty seven (87) diabetic male subjects (mean age: 74+/-7 years) with proven CAD were randomized to a 12 week treatment with either T undecanoate (40 mg administered three daily) or placebo (P) in a double blind protocol. Weekly episodes of angina attacks, number of ischemic episodes daily and total ischemic burden on ambulatory ECG Holter were evaluated at baseline and at the end of the study. Serum total cholesterol and triglyceride concentrations were also measured at the same time points. Compared to P, T significantly reduced the number of anginal attacks/weeks of 34% (p<0.05); the silent ischemic episodes of 26% (p<0.05), and the total ischemic burden of 21% (p<0.05) on ambulatory ECG monitoring. After 12 weeks total cholesterol, plasma triglycerides and HOMA index were significantly reduced in the T group compared to P group.

Conclusions: Three months administration of T has beneficial effect on serum cholesterol and triglyceride levels in patients with CAD and reduces the number of anginal attacks, and ischemic episodes. These effect may be related to the metabolic and vasoactive properties of the hormone. Further studies are needed in order to assess the long term relevance of these effects.
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http://dx.doi.org/10.1016/j.ijcard.2008.12.107DOI Listing
June 2010

Endothelial effects of drugs designed to treat erectile dysfunction.

Curr Pharm Des 2008 ;14(35):3768-78

Internal Medicine Unit, Medical Pathophysiology Department, Sapienza University of Rome, Viale del Policlinico 155, Rome, Italy.

Erectile dysfunction (ED) and endothelial dysfunction are common in individuals with multiple cardiovascular risk factors (CRFs) and are longitudinal predictors of cardiovascular events. ED is associated with systemic endothelial cell activation/dysfunction independent from CRFs or from diffuse, unrecognized vascular damage. The pathogenesis of endothelial dysfunction and ED is intimately linked through decreased expression and activation of endothelial nitric oxide (NO) synthase and the subsequent physiologic actions of NO. Furthermore, reduced biologic activity of endothelium-derived NO links atherosclerosis to ED and underscores the role of altered endothelium in the pathogenesis of both conditions. Evidence-based data suggest that daily use of phosphodiesterase type-5 inhibitors (PDE5-i) improves endothelial and erectile functions and that this benefit is lost upon drug withdrawal. Daily PDE5-i may also improve lower tract urinary symptoms related to benign prostatic hyperplasia through a reduction of adrenergic overtone. The relevance for these drugs in the prevention of complications in internal medicine diseases, i.e. cardiovascular disease, clotting disorders and autoimmune disease is uncertain. Finally, endothelial dysfunction is present in testosterone deficiency syndromes and replacement therapy is able to revert ED and to improve endothelial function. Aim of the present review is to discuss the systemic effects of drugs designed to treat ED, such as testosterone and PDE5-i, with regard to safety, unwanted effects and efficacy in improving endothelial function; finally, a goal-oriented approach to rehabilitation using daily vs. on-demand PDE5-i in difficult patients is discussed.
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http://dx.doi.org/10.2174/138161208786898725DOI Listing
March 2009

Platelet-derived growth factor receptor beta-subtype regulates proliferation and migration of gonocytes.

Endocrinology 2008 Dec 7;149(12):6226-35. Epub 2008 Aug 7.

Department of Medical Physiopathology, Sapienza University, Policlinico Umberto I, 00161 Rome, Italy.

Proliferation and migration of gonocytes, the precursors of spermatogonial stem cells, to the germline niche in the basal membrane of the seminiferous tubules, are two crucial events that take place between postnatal d 0.5 (P0.5) and P5.0 in the mouse and involve a selection of the cells that are committed to the germline stem cells lineage. Here we show that from embryonic d 18.0 (E18) and up to P5, the gonocytes express platelet-derived growth factor (PDGF) receptor beta-subtype (PDGFR-beta) and that during the same time period, the Sertoli cells express PDGF-B and PDGF-D, both ligands for PDGFR-beta. Inhibition of the PDGFR-beta tyrosine kinase activity during the first five postnatal days provokes a profound reduction of gonocyte number through inhibition of their proliferation and induction of apoptosis. Moreover, we found that PDGFR-beta ligands are chemotactic for gonocytes. These data suggest that PDGFR-beta activation has the remarkable capability to drive the selection, survival, and migration of the gonocytes from the center of the seminiferous tubules to the testicular germline niche on the basal membrane.
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http://dx.doi.org/10.1210/en.2008-0349DOI Listing
December 2008

TEQ(S) and body burden for PCDDs, PCDFs, and dioxin-like PCBs in human adipose tissue.

Chemosphere 2008 Aug 27;73(1):92-6. Epub 2008 Jun 27.

Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), mono-ortho and non-ortho polychlorinated biphenyls (dioxin-like PCBs) were determined in samples of human fat tissue from nine Italian obese patients. The toxicity equivalent (TEQ) values ranged from 9 to 25 pg TEQ g(-1) lipid (WHO-TEF values, 2005 [Van den Berg, M., Birnbaum, L.S., Denison, M., De Vito, M., Farland, W., Feeley, M., Fiedler, H., Hakansson, H., Hanberg, A., Haws, L., Rose, M., Safe, S., Schrenk, D., Tohyama, C., Tritscher, A., Tuomisto, J., Tysklind, M., Walker, N., Peterson, R.E., 2006. The 2005 World Health Organization reevaluation of human and mammalian Toxic Equivalency Factors for dioxins and dioxin-like compounds. Toxicol. Sci. 93, 223-241]), the contribution of dioxin-like PCBs was more than 30% of the total TEQ values. The obese body burdens varied from 6 to 11 ng TEQ kg(-1) body weight (BW), exceeding the estimated steady-state body burden 5 ng TEQ kg(-1) BW, based on lipid adjusted serum concentrations from several populations in the mid-1990s, calculated in the risk assessment US EPA document.
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http://dx.doi.org/10.1016/j.chemosphere.2008.04.088DOI Listing
August 2008

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

Impairment of diastolic function in adult patients affected by osteogenesis imperfecta clinically asymptomatic for cardiac disease: casuality or causality?

Int J Cardiol 2009 Jan 18;131(2):200-3. Epub 2008 Jan 18.

Dipartimento di Fisiopatologia Medica,Cattedra di Medicina Interna, Università degli Studi di Roma La Sapienza, Italy.

Osteogenesis imperfecta (OI) is a rare inherited connective disorder causing increased bone fragility and low bone mass. OI includes severe bone fragility, impaired dentinogenesis, with less common alterations in the joints, blood vessels, heart valves, skin. Interestingly, description of left ventricular rupture, aortic dissection and heart valves incompetence has been previously described. Death may occur in OI patients for cardiac disease in asyntomatic subjects. Aim of our study has been to evaluate the presence of potential subclinical cardiac disorders and to characterize cardiac functional parameters by echocardiography in adults with OI in absence of cardiac symptoms. Forty patients (21 females and 19 males) affected by type I, III, IV OI and 40 control subjects (20 females and 20 males) were evaluated in the study. Patients and controls underwent clinical examination, screening for endocrine and metabolic disorders, 12-lead electrocardiogram and echocardiogram. In particular, all subjects were evaluated by two-dimensional echocardiography with continuous- and pulse-wave Doppler. Patients and controls belonged to NYHA class I and no significant electrocardiographic alteration was documented in both groups. Thirty-eight patients (95%) showed valvular regurgitation compared to one control subject (2.5%; P<0.001). As regards the diastolic function parameters, in OI patients E wave velocity was reduced by 23% (95% CI: 9% to 29%; P<0.001), E/A ratio was reduced by 17% (95% CI: 15% to 26%; P<0.001) while isovolumetric relaxation time (IRT) was increased by 47% (95% CI: 26% to 53%; P<0.001) and E wave deceleration time (DT) was increased by 18% (95% CI: 13% to 26%; P<0.001) compared to controls. In conclusion, our data indicate that adult patients affected by OI have an altered diastolic function in absence of other metabolic alterations. These diastolic echocardiographic parameters might worsen over time, especially if other cardiovascular risk factors (e.g., smoking, hypertension, metabolic and endocrine alterations) are not carefully checked, monitored and treated. In the context of a multidisciplinary evaluation of OI patients, our data suggest that a careful cardiological evaluation of these patients is indicated beside skeletal evaluation and therapeutical skeletal options.
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http://dx.doi.org/10.1016/j.ijcard.2007.10.051DOI Listing
January 2009

Glucocorticoid-induced osteoporosis: an osteoblastic disease.

Aging Clin Exp Res 2007 Jun;19(3 Suppl):5-10

Dipartimento di Fisiopatologia Medica, Policlinico Umberto I, Università degli Studi di Roma La Sapienza, 00166 Roma, Italy.

It is well-known that glucocorticoid-induced osteoporosis (GIO) is the most common form of secondary osteoporosis. It is estimated that 30% to 50% of patients receiving chronic glucocorticoid therapy suffer vertebral or hip fractures, which are often asymptomatic. Vertebral fractures occur early after exposure to glucocorticoids, at a time when bone mineral density (BMD) declines rapidly. Glucocorticoids impair osteoblast homeostasis and induce apoptosis of both osteoblasts and osteocytes, leading to suppression of bone formation. Glucocorticoids also favor osteoclastogenesis and, as a consequence, increase bone resorption. The end-point of these alterations is a net decrease in BMD and alterations in bone quality. Bisphosphonates have been approved for both prevention and treatment of GIO. At the present time, anabolic therapeutic agents are still under investigation.
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June 2007

The differential effects of bisphosphonates, SERMS (selective estrogen receptor modulators), and parathyroid hormone on bone remodeling in osteoporosis.

Clin Interv Aging 2007 ;2(1):55-64

Cattedra di Medicina Interna, Dipartimento di Fisiopatologia Medica, Università degli Studi di Roma La Sapienza, Italy.

Osteoporosis is a skeletal metabolic disease characterized by a compromised bone fragility, leading to an increased risk of developing spontaneous and traumatic fractures. Osteoporosis is considered a multifactorial disease and fractures are the results of several different risk factors both extra- and intraskeletal. Thus bone fragility can be the end point of several different causes: a) failure to reach an optimal peak bone mass during growth; b) excessive bone resorption resulting in decreased bone mass and microarchitectural deterioration; c) inadequate formation upon an increased resorption during the process of bone remodeling. The pharmacological therapeutical options, available to date, are directed on prevention of fractures. The aim of this paper is to describe the activities and the mechanisms of action, as known at present, of the most used therapies for osteoporosis and their clinical implications. Improvement of knowledge in this field will allow us to further improve therapeutical choices and pharmacological interventions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684086PMC
http://dx.doi.org/10.2147/ciia.2007.2.1.55DOI Listing
January 2008

A new heterozygous mutation (R714C) of the osteopetrosis gene, pleckstrin homolog domain containing family M (with run domain) member 1 (PLEKHM1), impairs vesicular acidification and increases TRACP secretion in osteoclasts.

J Bone Miner Res 2008 Mar;23(3):380-91

Department of Experimental Medicine, University of L'Aquila, Italy.

Unlabelled: We studied phenotypic and cellular aspects in a patient with a heterozygous mutation of the PLEKHM1 gene and obtained some indications regarding the role of the protein in bone cell function. Plekhm1 is involved in osteoclast endosomal vesicle acidification and TRACP exocytosis, contributing to events involved in osteoclast-osteoblast cross-talk.

Introduction: The gene PLEKHM1 encodes a nonsecretory adaptor protein that localizes to endosomal vesicles. A highly truncated Plekhm1 protein was previously found in a patient with intermediate autosomal recessive osteopetrosis.

Materials And Methods: We describe a new heterozygous mutation in the PLEKHM1 gene in a patient presenting with low vertebral and femoral T-scores and areas of focal sclerosis. Clinical evaluation, mutational analysis, assessment of in vitro osteoclast morphology and activity, transfection studies, and evaluation of osteoclast-osteoblast cross-talk were carried out.

Results: Direct DNA sequencing showed a heterozygous C to T substitution on cDNA position 2140 of the PLEKHM1 gene, predicted to lead to an R714C mutant protein. The mutation was not found in 104 control chromosomes. In vitro, patient's osteoclasts showed normal formation rate, morphology, number of nuclei, and actin rings but lower TRACP activity and higher endosomal pH than control osteoclasts. The patient had high serum PTH and TRACP, despite low TRACP activity in osteoclasts in vitro. HEK293 cells overexpressing either wildtype or Plekhm1-R714C showed no difference in localization of the variants, and co-transfection with a TRACP vector confirmed low TRACP activity in cells carrying the R714C mutation. RAW 264.7 osteoclast-like cells expressing the Plekhm1-R714C variant also showed low TRACP activity and reduced ability to acidify endosomal compartments compared with cells expressing the wildtype protein. Reduced intracellular TRACP was caused by increased protein secretion rather than reduced expression. TRACP-containing conditioned medium was able to increase osteoblast alkaline phosphatase, suggesting the focal osteosclerosis is a result of increased osteoclast-osteoblast coupling.

Conclusions: We provide further evidence for a role of Plekhm-1 in osteoclasts by showing that a novel mutation in PLEKHM1 is associated with a complex bone phenotype of generalized osteopenia combined with "focal osteosclerosis." Our data suggest that the mutation affects endosomal acidification/maturation and TRACP exocytosis, with implications for osteoclast-osteoblast cross-talk.
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http://dx.doi.org/10.1359/jbmr.071107DOI Listing
March 2008

Erectile dysfunction in systemic sclerosis: effects of longterm inhibition of phosphodiesterase type-5 on erectile function and plasma endothelin-1 levels.

J Rheumatol 2007 Aug 1;34(8):1712-7. Epub 2007 Jul 1.

Department of Clinical Immunology and Allergy, Department of Medical Pathophysiology, University of Rome La Sapienza, Rome, Italy.

Objective: To investigate the effects of prolonged inhibition of phosphodiesterase type-5, using once-daily long-acting phosphodiesterase type-5 inhibitor (tadalafil) on erectile function and biomarkers of endothelial function in male patients with systemic sclerosis (SSc) and erectile dysfunction (ED).

Methods: In an open-label study, 14 nonconsecutive male patients with SSc with different degrees of ED were enrolled into the study irrespective of their clinical response to tadalafil, and received once-daily tadalafil 10 mg for 12 weeks. Primary endpoints were variations from baseline of penile arterial inflow [peak systolic velocity (PSV, cm/s); measured with dynamic color duplex ultrasound] and the erectile function domain score (measured with the International Index of Erectile Function questionnaire). Secondary endpoints were variations from baseline of morning erections (determined by modified question 13 of the Structured Interview on Erectile Dysfunction questionnaire) and plasma concentrations of endothelin-1 (ET1).

Results: The PSV and the erectile function domain score were significantly improved by once-daily tadalafil (from 21.3 +/- 6.4 to 30.0 +/- 7.0 cm/s and from 13.0 +/- 6.8 to 17.0 +/- 9.0 vs baseline, respectively; p <0.05). Question 13 scores decreased dramatically after treatment compared with baseline (from 2.2 +/- 0.2 to 0.8 +/- 0.5 arbitrary units; p < 0.001), and plasma ET1 levels decreased (from 24 +/- 15 to 9.8 +/- 7.4 pg/ml; p < 0.05).

Conclusion: In men with SSc-related ED, once-daily tadalafil improved both erectile function and vascular measures of cavernous arteries. Increases in morning erections and decreases in plasma ET1 levels were found, which may play a potential role in preventing progression of penile fibrosis and erectile dysfunction.
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August 2007

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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