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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. Francomano D, Greco EA, Lenzi A, and Aversa A. CAG repeat testing of androgen receptor polymorphism: Is this necessary for the best clinical management of hypogonadism? J Sex Med 2013;10:2373–2381.

Erectile dysfunction (ED) prevalence in men with systemic sclerosis (SSc) is high and can be considered a manifestation of endothelium damage.This study aims to correlate ED with endothelial dysfunction and digital vascular damage in SSc patients.The main outcome measures were erectile function, Doppler indices of cavernous arteries, flow-mediated dilation (FMD), capillaroscopic damage, skin perfusion, and digital pulsatility.In 23 SSc patients, erectile function was investigated using the International Index of Erectile Function-5 (IIEF-5). Doppler indices of cavernous arteries, peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI) were measured at the penoscrotal junction before and after pharmacostimulation with 20 mg prostaglandin E1. FMD and nailfold videocapillaroscopy (NVC) were used to evaluate endothelial dysfunction and capillaroscopic damage. Skin perfusion and digital sphygmic waves were measured by laser Doppler perfusion imaging (LDPI) and digital photoplethysmography (PPG), respectively.IIEF-5 score was reduced in 83% of patients. PSV was reduced in 96%, while EDV was increased in 48% of patients. A positive correlation was observed between IIEF-5 score and FMD (r = 0.71, P 0.0001) and between the former and PSV (r = 0.76, P 0.0001). A negative correlation was observed between EDV and FMD (r = -0.509, P 0.01). FMD and Doppler indices were reduced with capillaroscopic damage progression. A positive correlation exists between LDPI perfusion and IIEF-5 score (r = 0.743, P 0.0001) and between the former and PSV (r = 0.714, P 0.0001), while a negative correlation is observed between LDPI perfusion and EDV (r = -0.677, P 0.0001). A positive correlation exists between PPG pulsatility and IIEF-5 score (r = 0.752, P 0.0001) and between the former and PSV (r = 0.747, P 0.0001), while negative correlation is observed between PPG pulsatility and EDV (r = -0.689, P 0.0001).In SSc patients, ED correlates with endothelial dysfunction and digital microvascular damage.

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

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.

The concept of testosterone (T) supplementation (TS) as a new anti-obesity medication in men with testosterone deficiency syndrome (TDS) is emerging. Data from placebo-controlled trials are more conflicting. The aim of this study is to systematically review and meta-analyze available observational and register studies reporting data on body composition in studies on TS in TDS.An extensive MEDLINE, Embase, and Cochrane search was performed including the following words: "testosterone" and "body composition." All observational studies comparing the effect of TS on body weight and other body composition and metabolic endpoints were considered.Out of 824 retrieved articles, 32 were included in the study enrolling 4513 patients (mean age 51.7 ± 6.1 years). TS was associated with a time-dependent reduction in body weight and waist circumference (WC). The estimated weight loss and WC reduction at 24 months were -3.50 [-5.21; -1.80] kg and -6.23 [-7.94; -4.76] cm, respectively. TS was also associated with a significant reduction in fat and with an increase in lean mass as well as with a reduction in fasting glycemia and insulin resistance. In addition, an improvement of lipid profile (reduction in total cholesterol as well as of triglyceride levels and an improvement in HDL cholesterol levels) and in both systolic and diastolic blood pressure was observed.Present data support the view of a positive effect of TS on body composition and on glucose and lipid metabolism. In addition, a significant effect on body weight loss was observed, which should be confirmed by a specifically designed RCT.

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.An extensive Medline search was performed.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.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.

Introduction Several hormones and neurotransmitters orchestrate men’s sexual response, including the appetitive (sexual desire) and consummative (arousal and penile erection) phases. Aim To provide an overview and recommendations regarding endocrinologic control of sexual desire and arousal and erection and their disturbances. Methods Medical literature was reviewed by the subcommittee of the International Consultation of Sexual Medicine, followed by extensive internal discussion, and then public presentation and discussion with other experts. The role of pituitary (prolactin, oxytocin, growth hormone, and α-melanocyte-stimulating hormone), thyroid, and testicular hormones was scrutinized and discussed. Main Outcome Measures Recommendations were based on grading of evidence-based medical literature, followed by interactive discussion. Results Testosterone has a primary role in controlling and synchronizing male sexual desire and arousal, acting at multiple levels. Accordingly, meta-analysis indicates that testosterone therapy for hypogonadal individuals can improve low desire and erectile dysfunction. Hyperprolactinemia is associated with low desire that can be successfully corrected by appropriate treatments. Oxytocin and α-melanocyte-stimulating hormone are important in eliciting sexual arousal; however, use of these peptides, or their analogs, for stimulating sexual arousal is still under investigation. Evaluation and treatment of other endocrine disorders are suggested only in selected cases. Conclusion Endocrine abnormalities are common in patients with sexual dysfunction. Their identification and treatment is strongly encouraged in disturbances of sexual desire and arousal.

Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD).Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression.Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation.Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

Men affected by multiple sclerosis often experience neurogenic overactive bladder (OAB), lower urinary tract symptoms and erectile dysfunction (ED). The aim of the study was to investigate modifications of urinary and sexual functions after administration of daily tadalafil (TAD) 5 mg. Twenty men were enrolled in a single-blind, 4-week prospective study while 10 men without treatment served as controls. Primary outcomes were changes from baseline of International Prostate Symptom (IPSS), OAB questionnaire (OAB-q-short form) and International Index of Erectile Function (IIEF-5) scores. To evaluate the influence of bladder filling on somatic reflexes, we studied variations of the H-reflex evoked by electrical stimuli applied to the tibial nerve at the popliteal fossa and recorded from the soleus muscle. Also testosterone/estradiol (T/E) ratio was measured before and after treatment. In TAD group, an improvement in IPSS (p

Introduction A well‐tailored testosterone replacement treatment (TRT) in male hypogonadal athletes plays a pivotal role to restore physiological performances, to reduce health risks, and to guarantee the ethic of competition. Few studies evaluated individual androgens profiles during TRT in trained individuals. Aim The aim of this article was to verify the efficacy in restoring eugonadal serum and urinary androgens profiles after testosterone enanthate (TE) and gel (TG) administration. Methods Ten male Caucasian‐trained volunteers affected by severe hypotestosteronemia ( Main Outcome Measures The main outcome measures of this article were serum total testosterone (TT), dihydrotestosterone (DHT), calculated free and bioavailable testosterone (cFT, cBioT), 17‐β‐estradiol, and urinary glucuronide testosterone metabolites. Results Supraphysiological TT concentrations were observed in 50% of our volunteers until 7 days after TE and in the 4% of total samples after TG. Serum DHT was high both after TE (all volunteers on day 7 and 50% on day 14) and during TG (32% of total samples). A relatively low number of samples showed normal cFT and cBioT both after TE and TG (20–44%, respectively). Urinary metabolites were related to the type of treatment and to serum androgens profile and resulted in the normal ranges from 15% to 60% of total samples. Conclusion Besides well‐known variations of mean serum TT, we showed a high percentage of serum and urinary samples with abnormal androgens, being TG safer than TE. We conclude that monitoring TRT with TT only may be inaccurate because of abnormal fluctuations of other circulating androgens. Further studies to identify the appropriate markers of eugonadism during TRT are highly warranted both in athletes and in non‐athletes. Di Luigi L, Sgro P, Aversa A, Migliaccio S, Bianchini S, Botre F, Romanelli F, and Lenzi A. Concerns about serum androgens monitoring during testosterone replacement treatments in hypogonadal male athletes: a pilot study. J Sex Med 2012;9:873–886.

Objective: Obesity negatively affects human health. Limiting food intake, while producing some weight loss, results in reduction of lean body mass. Combined with moderate exercise it produces significant weight loss, maintains lean body mass and improves insulin sensitivity, but appears difficult to adhere to. Bariatric surgery is clinically effective for severely obese individuals compared with non-surgical interventions, but has limitations. Clinical and pre-clinical studies have implicated a role for testosterone (T) in the patho-physiology of obesity. Methods: Evidence Acquisition and Synthesis: A literature search in PubMed on the role of T in counteracting obesity and its complications. Results: Obesity per se impairs testicular T biosynthesis. Furthermore, lower-than-normal T levels increase accumulation of fat depots, particularly abdominal (visceral) fat. This fat distribution is associated with development of metabolic syndrome (MetS) and its sequels, namely type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). T treatment reverses fat accumulation with significant improvement in lean body mass, insulin sensitivity and biochemical profiles of cardiovascular risk. The contribution of T to combating obesity in hypogonadal men remains largely unknown to medical professionals managing patients with obesity and metabolic syndrome. Many physicians associate T treatment in men with risks for prostate malignancy and CVD. These beliefs are not supported by recent insights. Conclusion: While overall treatment of obesity is unsuccessful, T treatment of hypogonadal men may be effective, also because it improves mood, energy, reduces fatigue and may motivate men to adhere to diet and exercise regimens designed to combat obesity.

Aims: Osteogenesis imperfecta (OI) is a rare inherited disorder causing low bone density and increased fragility. Bisphosphonates (BP) are a treatment of choice for OI. Few studies have investigated the long-term effects of BP in OI patients. Thus, aim of our study was to follow up adults affected by OI to evaluate changes in metabolic, clinical situation and safety of long-term neridronic acid therapy, BP authorized for OI treatment. Study design: Longitudinal observational study. Place and duration of the Study: Department of Experimental Medicine, Section of Medical Pathophysiology, Endocrinology and Nutrition. Year: 2004 - October 2010. Methodology: 68 patients underwent clinical examination, laboratory endocrine/ metabolic, pro-inflammatory cytokines screening, ECG at baseline and every 3 months and bone mineral density evaluation, by DEXA, once a year. Results: Skeletal evaluation showed a significant increase of BMD through follow up. Patients were evaluated for metabolic and cardiovascular risk factors, which were unmodified by long-term therapy. Conclusion: Long-term neridronic acid treatment increases bone density, does not alter metabolic parameters indicating that this therapy can be considered safe and a valid therapeutic option for OI patients.

Premature ejaculation (PE) is a common ailment in men but its pathophysiology remains unclear. Updated guidelines from the International Society of Sexual Medicine attempt to aid the diagnosis and treatment of PE, and here we give our opinion on the best course of action for affected patients.

The application of digital pulse amplitude by fingertip peripheral arterial tonometry (PAT) device in patients with erectile dysfunction (ED) has never been performed. We investigated the diagnostic value of reactive hyperaemia (RH) and augmentation index (AI) as evaluated using PAT in men with ED of any origin. A total of 40 patients underwent diagnostic investigation for ED, including dynamic penile duplex ultrasound (PDU) and PAT device. Moreover, 30 patients without ED served as controls. According to PDU cutoff at 35 cm/sec, patients were divided into vascular (n = 30) and nonvascular (n = 10) ED aetiology. Moreover, controls with (n = 10) or without (n = 20) vascular risk factors (VRFs) were studied in a separate analysis. Average RH-PAT was not different in men with or without ED (P = 0.56) independently of VRFs. The AI was higher in men with ED compared with the controls (P < 0.0001) as well as when controlled for the presence or absence of VRFs (P < 0.0001). An inverse relationship between AI and PSV was also found (r² = -0.72, P < 0.0001). In conclusion, an increased AI but not an impaired RH-PAT is present in men with vascular ED independently of VRFs and may represent an early detection of vascular impairment that may precede endothelial dysfunction in populations at low risk for developing vascular ED.

Several studies suggest that type 2 diabetes mellitus (T2DM) is often associated with male hypogonadism. Despite the well-known link, the role of testosterone replacement therapy (TRT) in T2DM has not been completely clarified. The aim of the present study was to analyse systematically the relationship between androgen levels and T2DM by reviewing and meta-analysing available prospective and cross-sectional studies. In addition, a specific meta-analysis on the metabolic effects of TRT in available randomized clinical trials (RCTs) was performed. An extensive Medline search was performed including the following words: 'testosterone', 'type 2 diabetes mellitus' and 'males'. Of 742 retrieved articles, 37 were included in the study. In particular 28, 5 and 3 were cross-sectional, longitudinal and interventional studies, respectively. A further unpublished RCT was retrieved from http://www.clinicaltrials.gov. T2DM patients showed significantly lower testosterone plasma levels in comparison with non-diabetic individuals. Similar results were obtained when T2DM subjects with and without erectile dysfunction were analysed separately. Meta-regression analysis demonstrated that ageing reduced, while obesity increased, these differences. However, in a multiple regression model, after adjusting for age and body mass index (BMI), T2DM was still associated with lower total testosterone (TT) levels (adjusted r = -0.568; p < 0.0001). Analysis of longitudinal studies demonstrated that baseline TT was significantly lower among patients with incident diabetes in comparison with controls (HR = -2.08[-3.57;-0.59]; p < 0.001). Combining the results of RCTs, TRT was associated with a significant reduction in fasting plasma glucose, HbA1c, fat mass and triglycerides. Conversely, no significant difference was observed for total and high-density lipoprotein cholesterol, blood pressure and BMI. The meta-analysis of the available cross-sectional data suggests that T2DM can be considered independently associated with male hypogonadism. Although only few RCTs have been reported, TRT seems to improve glycometabolic control as well as fat mass in T2DM subjects.

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.

Context Erectile dysfunction (ED) is often the manifestation of a generalized vascular disorder characterized by endothelial dysfunction. Reduced biological activity of endothelium-derived nitric oxide links human atherosclerosis to ED and underscores the role of an altered endothelium in the pathogenesis of both conditions. Objective This review will provide an update on clinical data available on drugs promoting endothelial health and repair with regard to sexual medicine. Evidence acquisition A comprehensive evaluation of available published data in full-length papers, identified in MedLine up to February 2008, was performed. Evidence synthesis Evidence indicates that angiotensin-converting-enzyme inhibitors, sartanes, statins, vitamins (C and E), and L-arginine are all effective drugs for improving endothelial dysfunction in clinical studies; real benefits of dietary vitamin supplements and nutraceuticals are questionable. Growing evidence suggests that continued use of phosphodiesterase type 5 inhibitors as well as adjunctive testosterone replacement in deficiency syndromes may be beneficial and may synergistically improve endothelial function in selected subjects. Conclusions Endothelially active drugs may serve as active treatment for both general and sexual health in men with increased cardiovascular risk. Further controlled studies are necessary to establish the real cost-effectiveness of such therapies and their impact on outcomes for patients.

Background: Cross-sex hormone treatment in male-to-female (M2F) transsexuals appears reasonably safe. Little is known about its long-term use. The aim of our study was to evaluate the effect of long-term high dose estrogens, plus the antiandrogen cyproterone acetate, on bone composition and on biochemical/hormonal parameters in M2F transsexuals. Methods: A retrospective analysis was performed on 45 young M2Fs (mean age 39.5 years; body mass index (BMI) = 22) receiving estrogens (previously 100 μg ethinyl estradiol, now 2–4 mg oral estradiol valerate/day or 100 μg transdermal estradiol/day) plus the antiandrogen cyproterone acetate 100 mg/day. Data were retrieved from 20 subjects after reassignment surgery (mean hormonal treatment duration 15.6 years). A complete hormonal and biochemical assessment, as well as bone biochemical markers (parathyroid hormone (PTH), calcium, phosphorus, alkaline phosphatase and plasma pyridinoline crosslinks), were evaluated. Bone mineral density (BMD) was measured us...

Objective Diabetic patients have a reduced endothelial response to phosphodiesterase-5 inhibitors. The aim of this study was to determine the effects of chronic therapy with sildenafil on endothelial function in patients with Type 2 diabetes mellitus (DM2). Methods In a double-blind, placebo-controlled parallel design, 20 patients without erectile dysfunction randomly received a loading dose of sildenafil (100 mg) for 3 days, followed by either sildenafil 25 mg three times a day (t.d.s.) for 4 weeks or sildenafil 25 mg t.d.s. for 4 days followed by placebo t.d.s. for 3 weeks. Results After 1 week, flow-mediated dilatation (FMD) improved significantly (> 50% compared with baseline) in patients allocated to both sildenafil arms (62 and 64%, respectively). In patients allocated to chronic sildenafil, a progressive increase in percentage of patients with FMD improvement was noted (78, 86 and 94% at 2, 3 and 4 weeks, respectively) while a progressive decrease in the placebo group occurred (45, 18 and 6% at 2, 3 and 4 weeks, respectively). At the end of the study, a significant improvement in FMD compared with baseline was noted after chronic sildenafil (FMD from 6.8 ± 0.5 to 12.5 ± 0.7%, P = 0.01 vs. baseline). A decrease in endothelin-1 levels and an increase in nitrite/nitrate levels were found after chronic sildenafil; significant changes from baseline in C-reactive protein, interleukin 6, intercellular adhesion molecule and vascular adhesion molecule levels were also found. Conclusions In DM2 patients, daily sildenafil administration improves endothelial function and reduces markers of vascular inflammation, suggesting that the diabetes-induced impairment of endothelial function may be improved by prolonged phosphodiesterase-5 inhibition. Diabet. Med. 25, 37–44 (2008)

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 increased expression and activation of endothelial nitric oxide (NO) synthase and the subsequent physiologic actions of NO. Reduced biologic activity of endothelium-derived NO links human atherosclerosis to ED and underscores the role of altered endothelium in the pathogenesis of both conditions. ED may be the only clinical marker of systemic endothelial damage that is associated with a documented future risk of acute cardiovascular events. Searching for ED might be relevant in men with CRFs and no other clinical atherosclerosis in order to identify patients who could benefit from phosphodiesterase type 5 inhibitors to reduce their cardiovascular risk while treating ED.

Despite increased global interest in testosterone deficiency in men and its treatment with testosterone therapy, practical aspects of care remain confusing to many practitioners. Testosterone deficiency can result from testicular dysfunction (primary hypogonadism) or hypothalamic-pituitary dysfunction (secondary hypogonadism), and be congenital or acquired. Sexual and nonsexual symptoms of testosterone deficiency can negatively affect quality of life and cause considerable general health concerns. Investigation of testosterone deficiency should be undertaken in men with symptoms of reduced libido, erectile dysfunction, depression, fatigue, poor concentration, and poor memory. Total and free testosterone are the most frequently used tests and evaluating serum concentrations of luteinizing hormone aids determination of primary versus secondary testosterone deficiency. Multiple formulations of testosterone therapy are available, but symptomatic benefits might not manifest for several weeks to many months; long-acting formulations are convenient and improve compliance. Concerns regarding cardiovascular and prostate cancer risks are not supported by current evidence, monitoring during therapy is mandatory. On balance, testosterone therapy can be considered a safe and effective treatment for testosterone deficiency.

In the treatment of complex paraclinoidal and giant cavernous aneurysms, preservation of the patency of the internal carotid artery (ICA) is not always possible, and therapeutic occlusion of the carotid is still an important option for their management. A complete preoperative evaluation of the carotid reserve circulation, including the use of temporary balloon occlusion test and single photon emission computerized tomography (SPECT) should be included in the current paradigms of paraclinoidal and intracavernous aneurysms management. We present a series of fifteen patients with sixteen giant or complex carotid cavernous or ophthalmic aneurysms that were treated following a protocol for our preoperative decision-making analysis. Extracranial to intracranial saphenous vein bypass was reserved to the cases where carotid occlusion would be associated with high risk of ischemic complications and was performed in three patients. Besides the difficulties in dealing with those complex aneurysms, good clinical outcome was possible in our experience with the designed paradigm. No tratamento de aneurismas paraclinoideos complexos e cavernosos gigantes, a preservação da patência vascular nem sempre é possível, e a oclusão terapêutica da carótida ainda é uma opção importante no seu manejo. Uma avaliação pré-operatória completa da reserva circulatória carotídea, incluindo o uso do teste de oclusão temporária por balão associado à tomografia computadorizada por emissão de fóton único (SPECT) podem ser de grande utilidade para definir a opção terapêutica a ser adotada. Nós apresentamos uma série de quinze pacientes com dezesseis aneurismas complexos ou gigantes do segmento oftálmico e cavernoso da artéria carótida, que foram tratados de acordo com determinado protocolo de investigação pré-operatória. Anastomose com enxerto de veia safena entre a carótida extra e intracraniana foi reservada para os casos em que a oclusão carotídea estaria associada a um alto risco de complicações isquêmicas e foi realizado em três pacientes. Apesar das dificuldades em lidar com aneurismas complexos como os aqui relatados, é possível obter um bom resultado clínico nestes pacientes com o paradigma desenhado.

Men with erectile dysfunction (ED) frequently have a disproportionate burden of comorbid vascular disorders including atherosclerotic disease. We investigated whether scheduled tadalafil is better than on-demand (OD) in improving endothelium-dependent vasodilatation of cavernous arteries in men with ED and whether this effect is also exerted on markers of endothelial function. We did an open-label, randomized, crossover study including 20 male outclinic patients aged 18 years or older (mean age 54 years) who had at least a 3-month history of ED of any severity or etiology. Tadalafil (20 mg) on alternate days (ADs) or OD was administered for 4 weeks. Primary end points were variations of basal inflow (peak systolic velocity (PSV)) and flow-mediated dilatation (FMD) of cavernous arteries compared with baseline at penile Duplex ultrasound. Secondary end points were variations of Q13-SIEDY scores regarding morning erections and of markers of endothelial function, that is, vascular cell adhesion molecule (VCAM), intercellular cell adhesion molecule, endothelin-1 (ET-1), insulin and C-reactive protein (CRP). PSVs and FMD were higher after AD treatment when compared with OD and baseline, respectively (P=0.0001), and improvements were maintained from 2 weeks after discontinuation (P

Historically, high androgen levels have been linked with an increased risk for coronary artery disease (CAD). However, more recent data suggest that low androgen levels are associated with adverse cardiovascular risk factors, including an atherogenic lipid profile, obesity and insulin resistance. The aim of the present study was to evaluate the relationship between plasma sex hormone levels and presence and degree of CAD in patients undergoing coronary angiography and in matched controls. We evaluated 129 consecutive male patients (mean age 58+/-4 years, range 43-72 years) referred for diagnostic coronary angiography because of symptoms suggestive of CAD, but without acute coronary syndromes or prior diagnosis of hypogonadism. Patients were matched with healthy volunteers. Out of 129 patients, 119 had proven CAD; in particular, 32 of them had one, 63 had two and 24 had three vessel disease, respectively. Patients had significantly lower levels of testosterone than controls (9.8+/-6.5 and 13.5+/-5.4 nmol/l, P

Hypogonadism may play a significant role in the pathophysiology of erectile dysfunction (ED). A threshold level of testosterone may be necessary for normal erectile function. Testosterone replacement therapy is indicated in hypogonadal patients and is beneficial in patients with ED and hypogonadism. Monotherapy with testosterone for ED is of limited effectiveness and may be most promising in young patients with hypogonadism and without vascular risk factors for ED. A number of laboratory and human studies have shown the combination of testosterone and other ED treatments, such as phosphodiesterase type 5 (PDE5) inhibitors, to be beneficial in patients with ED and hypogonadism, who fail PDE5 inhibitor therapy alone. There is increasing evidence that combination therapy is effective in treating the symptoms of ED in patients for whom treatment failed with testosterone or PDE5 inhibitors alone. Testosterone replacement therapy has potentially evolved from a monotherapy for ED in cases of low testosterone, to a combination therapy with PDE5 inhibitors. Screening for hypogonadism may be useful in men with ED who fail prior PDE5 inhibitors, especially in populations at risk for hypogonadism such as type 2 diabetes and the metabolic syndrome.

Introduction. It has been reported that lack of sexual activity due to erectile dysfunction (ED) may be associated with testosterone (T) decline. Aim. To investigate whether the known changes in sex hormones associated with resumption of sexual activity are sustained in the long term. Main Outcome Measures. Primary endpoints were variations from baseline of steroid hormones: total T, free T (f T), and estradiol (E). Secondary endpoints were variations of erectile function domain scores at International Index of Erectile Function-5 (IIEF-5). Methods. In an open-label fashion, 20 patients (mean age 54.8 ± 8.4 years) received tadalafil 10-20 mg on demand for 12 months. Exclusion criteria were those reported for phosphodiesterase inhibitors, including hypogonadism and hyperprolactinemia. Results. Tadalafil assumption was safe and well tolerated (overall adverse effects in 15% of patients) and none discontinued medication. A significant decrease in E levels occurred at the end of the study (from 19.9 ± 9.6 to 16.6 ± 8.1 ng/dL, P = 0.042 vs. baseline), with parallel increase in the T:E ratio (26.3 ± 15.3 to 32.6 ± 17.7, P = 0.05), whereas no changes in T and f T serum levels were observed, respectively (411.4 ± 131.4 to 434.2 ± 177.1 ng/dL and 47.7 ± 15.3 to 49.9 ± 19.1 pmol/L, not significant). Interestingly, nonparametric subgroup analysis for related samples revealed that E decrease was detectable only in lean (N = 14) but not in obese (N = 6, body mass index > 27.5 kg/m 2 ) subjects (17.8 ± 10.1 vs. 13.5 ± 6.8, P < 0.05). A net increase in IIEF-5 scores was observed at the endpoint (13.7 ± 5.9 vs. 25.7 ± 2.9, P < 0.0001). Conclusions. Sustained improvement in sexual function after 12 months of tadalafil administration is associated with increased T:E ratio mainly related to reduction of E levels. We hypothesize that androgen-estrogen cross-talk and possible inhibition of aromatase activity during chronic exposure to tadalafil might have a role in the regulation of erectile function. Greco EA, Pili M, Bruzziches R, Corona G, Spera G, and Aversa A. Testosterone:estradiol ratio changes associated with long-term tadalafil administration: A pilot study. J Sex Med 2006;3:716-722.

Introduction Systemic sclerosis is a connective tissue disease characterized by Raynaud's phenomenon, degenerative changes and vascular lesions in the presence of thickened, sclerotic skin lesions determined by cellular proliferation, and excess of extracellular matrix production. The role of ultrasound in the investigation of penile pathology is well established as vasculogenic impotence accounts for more than 30% out of overall causes. Aim In this article, we report for the first time the extent of penile vascular damage in a series of 15 sclerodermic patients (mean age 47 ± 12.5 SD) under current treatment for their disease irrespective of their sexual dysfunction complaints. Methods After disease classification (mean duration of disease 7.2 ± 5.1 years), all patients were interviewed about the presence or absence of erectile dysfunction (ED) by using the Sexual Health Inventory for Men (SHIM) questionnaire, and then blood flow velocity in the cavernous artery following standardized pharmacostimulation was determined with Duplex ultrasonography along with the intima media thickness (IMT) of the common carotid artery, a valid index for atherosclerosis. Results Mean SHIM scores revealed the presence of moderate‐to‐severe ED (mean 13.3 ± 6.3). Interestingly, in all patients diffuse hyperechoic “spots” inside the corpora cavernosa along with thickening of the tunica albuginea were found. Severely impaired mean peak systolic velocities (20.2 ± 5.5 cm/second) in the presence of mild venous leakage as expressed by mean end diastolic velocities (4.6 ± 2.9 cm/second) were found along with normal IMT (0.065 ± 0.010 cm) and acceleration time (92.3 ± 32.7 cm/second). Conclusion Penile fibrosis almost invariably occurs in sclerodermic patients and this determines incomplete penile arterial and smooth muscle cell relaxation and ED despite the absence of indirect signs of early atherosclerosis, that is, abnormal IMT and acceleration time. Aversa A, Proietti M, Bruzziches R, Salsano F, and Spera G. The penile vasculature in systemic sclerosis: a Duplex ultrasound study. J Sex Med 2006;3:554–558.

Background Fifty-one patients with cervical spondylotic myelopathy (CSM) treated by anterior cervical corpectomy with fusion (ACWF) at our institution were included in a study during a period of 10 years to evaluate neurological, anatomical, and functional outcomes including satisfaction levels. Methods We have completed a prospective evaluation of 39 patients with spondylotic myelopathy submitted to ACWF during the period of 1989-2000. The data were analyzed for age, duration of symptoms, severity of preoperative neurological deficit, and single-level or multilevel compressive status looking for possible association with prognostic surrogate data and clinical outcome that were evaluated with the Nurick score and a survey of level of satisfaction. Results Of the 51 patients, 39 fullfilled the intended follow-up being 28 men (71.8%) and 11 women (28.2%). The average age was 63.5 years. Duration of symptoms ranged from 1 to 240 months (mean, 38.1 months). The mean preoperative Nurick scale score was 2.97; the mean postoperative score was 2.1. The most frequently involved vertebral body was C5 (71.7%). The follow-up period was longer than 18 months for all patients. Postoperative nonneurological complications occurred in 8 patients (15.6%). The mortality rate was 1.9% (n = 1). Postoperative results showed improvement in 25 patients (64.1%), no change in 13 (33.3%), and worsening in 1 (2.6%). The correlation coefficient of preoperative and postoperative Nurick scores was 0.733 (R2 = 0.53). Of the 39 patients, 31 answered the questionnaire for quality of life—19 (61.2%) were very satisfied, 6 were satisfied (19.35%), and 6 were not satisfied (19.35%). Conclusion Most patients (80.6%) were very satisfied or satisfied with the outcome and would decide again for the surgery (87%) if the results were previously known. Anterior cervical corpectomy with fusion was a reliable and rewarding procedure for CSM, with functional improvement in most patients. Excellent long-term outcome results in cervical fusion can be achieved without the use of hardware instrumentation.

By real-time RT-PCR and Western blot analysis, we found that phosphodiesterase type 5 (PDE5) mRNA and protein abundance was several fold higher in human male than in female reproductive tracts. The highest mRNA level (1 x 10(7) molecules/microg total RNA) was detected in human corpora cavernosa (CC), where PDE5 protein was immunolocalized in both muscular and endothelial compartment. The possible role of androgens in regulating PDE5 expression was studied using a previously established rabbit model of hypogonadotropic hypogonadism. In this model, hypogonadism reduced, and testosterone (T) supplementation restored, CC PDE5 gene and protein expression. In addition, T supplementation completely rescued and even enhanced cyclic GMP conversion to metabolites, without changing IC(50) for sildenafil (IC(50) = 2.16 +/- 0.62 nm). In control CC strips, sildenafil dose-dependently increased relaxation induced by electrical field stimulation, with EC(50) = 3.42 +/- 1.7 nm. Hypogonadism reduced, and T increased, sildenafil effect on electrical field stimulation, again without changing their relative EC(50) values. CC sensitivity to the NO-donor NCX4040 was greater in hypogonadal rabbit strips than in control or T-treated counterparts. Moreover, sildenafil enhanced NCX4040 effect in eugonadal rabbit strips but not in hypogonadal ones. This suggests that androgens up-regulate PDE5 in rabbit penis. We also measured PDE5 gene expression and metabolic activity in human CC from male-to-female transsexual individuals, chronically treated with estrogens and cyproterone acetate. Comparing the observed values vs. eugonadal controls, PDE5 mRNA, protein, and functional activity were significantly reduced. In conclusion, we demonstrated, for the first time, that androgens positively regulate PDE5, thus providing a possible explanation about the highest abundance of this enzyme in male genital tract.

Background Optochiasmatic tuberculomas are very rare lesions. They can occur with concomitant tuberculous meningitis, and pulmonary tuberculosis or as the only manifestation of the disease. The authors present a case of optic pathways tuberculoma with radiologic appearance simulating an optic pathways glioma. Case description We report a case of a 20-year-old man with mental retardation due to anoxic encephalopathy who developed a sudden bilateral amaurosis. He also presented with diabetes insipidus, panhypopituitarism, right proptosis, and chemosis. Computed tomography (CT) and magnetic resonance imaging (MRI) showed an enhancing lesion in the optochiasmatic region extending to both optic nerves, with a mass in the right orbit, mimicking an optic pathways glioma. There was no other evidence of systemic involvement of the tuberculosis. The lesion was explored through a right pterional transylvian approach with opening of the optic canal and orbital roof, and a biopsy and an internal decompression were performed. Histopathological studies demonstrated a granulomatous lesion with central caseous necrosis with acid-fast bacilli. The patient improved after treatment with tuberculostatic drugs, but vision recovery could not be achieved. Conclusion Visual compromise in tuberculosis is associated with hydrocephalus, optical neuritis or tuberculomas involving the optic pathways. Reviewing the literature on tuberculomas of the optochiasmatic area, we could not find any other case with such extensive involvement of the optic pathways that was radiologically suggestive of an infiltrating glioma. Histopathological studies remain crucial in the diagnosis of intrinsic expansive processes of the optochiasmatic region.

Summary objectives We have recently shown that, in men with erectile dysfunction (ED), free testosterone (FT) directly correlates with penile arterial inflow. This led us to further investigate the effect(s) of androgen administration on cavernous arteries in patients failing sildenafil treatment. design Prospective randomized placebo-controlled pilot study. patients Twenty patients with arteriogenic ED as evaluated by dynamic colour duplex ultrasound (D-CDU) studies, normal sexual desire but testosterone (T) and FT in the lower quartile of normal range (low-normal), not responding to sildenafil treatment (100 mg) on six consecutive attempts. measurements All patients had D-CDU, hormonal [LH, prostate-specific antigen (PSA), total and free testosterone, sex hormone-binding protein (SHBG), oestradiol], biochemical [haematocrit, low-density lipoprotein (LDL) and HDL cholesterol, triglycerides], and sexual evaluations [International Index of Erectile Function (IIEF)] before and after 1 month of therapy with transdermal testosterone (5 mg/day, n = 10) or placebo along with sildenafil treatment on demand. Measurement of flow parameters by D-CDU on cavernous arteries was the primary endpoint of the study. Improvement of erectile function was assessed using the IIEF questionnaire and the Global Assessment Question (GAQ). results One month treatment with transdermal testosterone led to a significant increase in T and FT levels (23·7 ± 3·3 SD vs. 12·8 ± 2·1 nmol/l and 473 ± 40·2 vs. 260 ± 18·1 pmol/l, P

We present a case of a 46-year old woman with a ventral epidural angiolipoma at the lumbosacral level with erosion of the sacrum. About ninety cases of spinal angiolipomas have been previously described in the literature, most of them situated on the thoracic region, dorsal to the dural sac. Angiolipomas can be radically excised with a good prognosis even in the presence of bone erosion. We did not find any other angiolipoma at the sacral level surgically explored in the review of the literature.

Diversos fatores têm sido associados ao desenvolvimento de edema peritumoral nos meningiomas. Foram estudados os aspectos radiológicos e anátomo-patológicos de 51 meningiomas intracranianos operados no Hospital Universitário Clementino Fraga Filho (HUCFF). Dois terços dos meningiomas apresentavam edema perilesional. O tamanho dos meningiomas correlacionou-se com a presença de edema, sendo mais frequente nos meningiomas grandes (>4cm). A localização parece, também, influenciar no desenvolvimento do edema peritumoral, sendo mais acentuado nos meningiomas da asa do esfenóide e incomum nos meningiomas do tubérculo selar. Os subtipos histológicos de meningioma não se correlacionaram com a intensidade do edema peritumoral. Dos diversos mediadores químicos descritos na literatura recente relacionados ao desenvolvimento de edema peritumoral em tumores intracranianos, destaca-se o fator de crescimento do endotélio vascular (VEGF). A expressão nos meningiomas do VEGF e de seu receptor flk-1 foi estudada com técnica imuno-histoquímica, demonstrando a sua expressão nas células tumorais.

Penile pharmacotesting (PPT) with alprostadil (PGE1) represents the most common diagnostic approach to male erectile dysfunction (ED). A positive response - i.e. normal erectile rigidity of sustained duration - is presumed to exclude venous or arterial pathology with enough accuracy. To test this assumption we compared PPT vs. flowmetric results obtained by colour-duplex Doppler ultrasound (CDDU) in patients (pts) undergoing diagnostic evaluation for ED under conditions of maximal cavernous relaxation. A total of 195 non-consecutive impotent pts were diagnosed after dynamic CDDU as non-vasculogenic (NOR), or having arteriogenic (AR), veno-occlusive (VO) or mixed (MX) ED. Maximal erection obtained after PPT was scored as: type-1 (full tumescence - no sustained rigidity, angle on the abdominal plane >90 degrees), type-2 (sustained partial erection, valid for intromission, angle=90 degrees) and type-3 (sustained full erection, angle

Background: The aim of this paper is to report on our surgical strategy and technique and to identify the best management for intracranial dermoids and epidermoids tumors (IDETs). Methods: We retrospectively reviewed 33 consecutive patients (14 males and 19 females; mean age at surgery, 37.9 years) with pathologically confirmed IDETs who underwent surgical resection, with mean follow-up of 7.2 years. Results: Gross total tumor removal was achieved in 24 cases (72.7%) with zero surgical mortality and a recurrence rate of 9%. Conclusions: The surgical strategies used in this group of patients enabled total removal of most tumors without surgical mortality and with low morbidity and recurrence rates, proving to be safe and effective.

Obesity is a widespread emergency in industrialised countries, and its incidence is expected to increase over the time. The presence of endocrine comorbidities in obese men is often neglected. Many studies have demonstrated that in severely obese patients a state of secondary ‘panhypopituitarism’ may occur, along with multiple endocrine peripheral defects, i.e. hypogonadism, sexual disturbances, vitamin D deficiency, osteoporosis and thyroid and growth hormone secretion disturbances. The recognition and appropriate treatment of these obesity-associated conditions is important to make the patient aware that weight loss and the achievement of the right body composition target is possible. Testosterone replacement therapy (TRT) in obese hypogonadal men is still a matter of debate because it is poorly understood whether obesity precedes or is rather the cause of reduced testicular function. The aim of this chapter will be to describe the pathophysiology of testicular dysfunctions occurring in obese men and the possibility to commence TRT in order to correct hypogonadism along with lifestyle modifications. Evidence-based medicine is growing up, and the most recent studies (controlled and uncontrolled) regarding efficacy and safety of TRT in obese men will be discussed.