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Introduction: Functional hypogonadism is frequently found in obese men, particularly those with metabolic complications. Several possible therapeutic approaches could be considered., Areas Covered: An extensive search on Medline, Embase, and Cochrane databases was performed to retrieve the available studies assessing the change of testosterone (T) and sexual function upon dieting or physical activity programs, as well as glucagon-like peptide 1 analogues. The role of lifestyle interventions associated with T replacement therapy (TRT) was also evaluated. The expert opinion provided here has been corroborated by meta-analyzing the results of the retrieved studies., Expert Opinion: Current evidence supports the beneficial role of lifestyle modifications in increasing T and improving sexual function as a function of weight loss. While dieting programs are associated with greater effects in younger populations, physical exercise has major effects in older ones. Among the dieting programs, a very low-calorie ketogenic diet shows the best results; aerobic or endurance physical exercise perform similarly. The advantages of functional hypogonadism in lifestyle modifications are empowered by the association with TRT. Therefore, TRT may be a valuable complementary strategy to increase muscle mass and facilitate physical exercise while improving sexual symptoms, thus favoring the motivation and compliance for lifestyle interventions.

Introduction: The specific role of testosterone (T) replacement therapy in patients with late onset hypogonadism is still conflicting. Several available preparations have been developed to restore either fertility and normal testosterone (T) levels (secondary hypogonadism) or just T levels (primary hypogonadism)., Areas Covered: Advantages and limitations related to available new treatments will be discussed in detail. In addition, possible news related to preparations in the pipeline will be discussed., Expert Opinion: The selection of a specific T preparation should be adequately discussed with each subject. Transdermal T preparations are those that can preserve, after a unique morning administration, the circadian rhythmicity of T secretion. Conversely, short-acting preparations (such as oral or intranasal) need two- or three-times daily administration, potentially reducing patient compliance. Long acting T preparations, such as injectable T undecanoate have the advantage of bimestrial or trimestral administration, reducing the required number of administrations. The use of non-steroidal selective androgen receptor modulators (SARM), a heterogeneous class of compounds selectively acting on androgen receptor targets, remains investigational due to the lack of the full spectrum of T's action and the possible risk of side effects, despite their potential use in the treatment of muscle wasting and osteoporosis.

Hypogonadism is frequent with a prevalence of 2% in the general population. Hypogonadism may derive from any condition able to disrupt the hypothalamic-pituitary-testis (HPT) axis at one or more levels. Hypogonadism may be classified according to the age of onset, its potential reversibility and level of the HPT axis damage. The latter categorization is useful to decide on the treatment. Damages to the hypothalamus-pituitary may benefit from either GnRH, gonadotropin or T therapy with the former carrying the advantage of stimulating spermatogenesis. Conversely, when the testis is damaged, T therapy is the only option and restoration of spermatogenesis is not possible. Therefore, the choice of therapy is primarily based on the diagnosis and patients' needs and both should be carefully considered., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Type 2 diabetes mellitus and pre-diabetes are associated with reduced circulating testosterone levels. However, the role of testosterone replacement therapy in these patients is still conflicting., Objectives: To summarize and critically analyze available data on the possible effect of testosterone administration in men with glucose abnormalities., Materials and Methods: A comprehensive systematic review was performed. When available, meta-analytic data were preferred. To better analyze the relationship between testosterone and the pre-diabetes condition, a systematic analysis was performed and the data obtained with the latter search were used for a meta-analytic approach. Finally, clinical data derived from a consecutive series of 4682 patients seeking medical care for sexual dysfunction at the University of Florence were also considered., Results: Patients with impaired fasting glucose were characterized by a 3 nmol/L lower level of total testosterone when compared to controls. Similarly, impaired fasting glucose was associated with a 1.8-fold increased risk of hypogonadism, when compared to subjects with normal glucose levels. Waist circumference and body mass index resulted as being the best predictors of reduced total testosterone levels. Secondary hypogonadism was two times higher in subjects with impaired fasting glucose when compared to rates observed in the general population. Testosterone replacement therapy was able to improve body composition, insulin resistance, and glucose profile both in impaired fasting glucose and type 2 diabetes mellitus whereas its role on body weight, lipid profile, and sexual function was less evident., Discussion and Conclusion: Weight loss and physical activities are able to improve both metabolic profile and testosterone levels. The combined approach of testosterone replacement therapy and lifestyle modifications could be suggested in symptomatic hypogonadal men to better motivate patients to perform physical activity which can eventually result in weight loss as well as metabolic profile and sexual function improvement. Whether or not these approaches can prevent the development of type 2 diabetes mellitus from pre-clinical conditions requires more studies., (© 2022 American Society of Andrology and European Academy of Andrology.)

Background: Klinefelter syndrome (KS) is frustratingly under-diagnosed. KS have a broad spectrum of clinical features, making it difficult to identify.  OBJECTIVE: We describe KS clinical presentation in a large Italian cohort., Design: This is the first observational cohort study within a national network, the Klinefelter ItaliaN Group (KING). Primary outcomes were to describe the basic clinical features and the actual phenotype of KS in Italy. Secondary outcomes were to determine age at diagnosis and geographical distribution., Methods: We performed a basic phenotyping and evaluation of the hormonal values of 609 adult KS patients., Results: Mean age at diagnosis was 37.4 ± 13.4 years. The overall mean testicular size was 3 ml, and 2.5 ml in both testes in untreated KS group. BMI was 26.6 ± 5.8 kg/m 2 , and 25.5% of KS had metabolic syndrome (MetS). LH and FSH were increased, and mean total testosterone were 350 ± 9.1 ng/dl. A descriptive analysis showed that 329 KS patients were evaluated in Northern Italy, 76 in Central and 204 in Southern Italy. Analysis of variance demonstrated significant statistical differences (p < 0001) between the age at diagnosis of the three geographical groups. Compared with the expected number among male patients matched for age in Italy, only 16% of KS patients received a diagnosis., Conclusions: These data are the results of the only national database available that collects the clinical and hormonal data of the KS patients, currently referred at the KING centers. In Italy the typical KS patient is overweight, with small testes, and elevated LH and FSH. Only 25.5% of them are diagnosed with MetS. Early detection and timely treatment are mandatory., (© 2022. The Author(s).)

Sexual symptoms are the most specific determinants of low testosterone (T) observed during adulthood. In this narrative review, we summarize the most important evidence supporting the positive relationships between endogenous T levels and sexual activity in the adult male, by using preclinical and clinical observations. In addition, we also report an update of our previous meta-analysis evaluating the effects of T treatment (TRT) on sexual functioning in subjects with T deficiency. Available data indicate that TRT of symptomatic hypogonadal men can improve several aspects of sexual life, including erection. However, the effect is rather modest and lower in subjects with associated metabolic conditions. The specific observed effects are similar to those derived from lifestyle intervention. Since TRT might result in body composition improvement, it is reasonable to suppose that an initial treatment with T can improve the willingness of hypogonadal subjects to perform physical exercise and to adhere to a healthier behavior. Similar data were derived from animal models. However, it should be important to recognize that lifestyle modifications should be the first step to promote weigh reduction. TRT can be combined with lifestyle interventions only in symptomatic hypogonadal subjects especially in the presence of comorbid metabolic conditions., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The role of testosterone (T) replacement therapy (TRT) in subjects with late onset hypogonadism is still the object of an intense debate., Methods: All observational studies and placebo-controlled or -uncontrolled randomized trials (RCTs) comparing the effect of TRT on different bone parameters were considered., Results: Out of 349 articles, 36 were considered, including 3103 individuals with a mean trial duration of 66.6 weeks. TRT improves areal bone mineral density (aBMD) at the spine and femoral neck levels in observational studies, whereas placebo-controlled RTCs showed a positive effect of TRT only at lumber spine and when trials included only hypogonadal patients at baseline (total testosterone < 12 nM). The effects on aBMD were more evident in subjects with lower T levels at baseline and increased as a function of trial duration and a higher prevalence of diabetic subjects. Either T or estradiol increase at endpoint contributed to aBMD improvement. TRT was associated with a significant reduction of bone resorption markers in observational but not in controlled studies., Conclusion: TRT is able to inhibit bone resorption and increase bone mass, particularly at the lumbar spine level and when the duration is long enough to allow the anabolic effect of T and estrogens on bone metabolism to take place., (© 2022. Italian Society of Endocrinology (SIE).)

Purpose: In both preclinical and clinical settings, testosterone treatment (TTh) of hypogonadism has shown beneficial effects on insulin sensitivity and visceral and liver fat accumulation. This prospective, observational study was aimed at assessing the change in markers of fat and liver functioning in obese men scheduled for bariatric surgery., Methods: Hypogonadal patients with consistent symptoms (n = 15) undergoing 27.63 ± 3.64 weeks of TTh were compared to untreated eugonadal (n = 17) or asymptomatic hypogonadal (n = 46) men. A cross-sectional analysis among the different groups was also performed, especially for data derived from liver and fat biopsies. Preadipocytes isolated from adipose tissue biopsies were used to evaluate insulin sensitivity, adipogenic potential and mitochondrial function. NAFLD was evaluated by triglyceride assay and by calculating NAFLD activity score in liver biopsies., Results: In TTh-hypogonadal men, histopathological NAFLD activity and steatosis scores, as well as liver triglyceride content were lower than in untreated-hypogonadal men and comparable to eugonadal ones. TTh was also associated with a favorable hepatic expression of lipid handling-related genes. In visceral adipose tissue and preadipocytes, TTh was associated with an increased expression of lipid catabolism and mitochondrial bio-functionality markers. Preadipocytes from TTh men also exhibited a healthier morpho-functional phenotype of mitochondria and higher insulin-sensitivity compared to untreated-hypogonadal ones., Conclusions: The present data suggest that TTh in severely obese, hypogonadal individuals induces metabolically healthier preadipocytes, improving insulin sensitivity, mitochondrial functioning and lipid handling. A potentially protective role for testosterone on the progression of NAFLD, improving hepatic steatosis and reducing intrahepatic triglyceride content, was also envisaged., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02248467, September 25th 2014.

Preliminary published data depict a much greater prevalence of males with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) referred for intensive care unit admission and severe sequelae in several countries. In this context, males seem to not only be more susceptible to the infection compared to female subjects, at least in Western countries, but their case fatality rate attributable to SARS-CoV-2 infection is also highest. Therefore, we may speculate that the different hormonal milieu could have a more profound pathophysiological role in association with SARS-CoV-2, with endogenous testosterone leaving men more prone to develop more serious complications related to the SARS-CoV-2 infection. Another option is that SARS-CoV-2 infection per se causes an acute stage of male hypogonadism, the depletion of androgenic action triggering serious or an even fatal course of the disease. Therefore, we strongly advocate the development of a prospective multidimensional andrological translational research project in men, which we called the PROTEGGIMI study. In this Opinion Article, we will not only highlight novel research activity in this area but also invite other researchers and learned scientific societies to join us in our efforts to understand an important and very newly discovered gap in knowledge, which may have serious implications for the lives of millions of men., (© 2020 American Society of Andrology and European Academy of Andrology.)

Background: Testosterone (T) plays a pivotal role in coordinating a series of psychological, cognitive and physical events that might (or might not) culminate in male sexual activity. In fact, T deficiency is associated, in a statistically significant way, with several sexual dysfunctions including erectile dysfunction (ED), reduction of spontaneous erection and hypoactive sexual desire (HSD). Although these associations are statistically significant, there is debate if they are also clinically meaningful. In addition, sexual dysfunctions are present also in several metabolic conditions - such as type 2 diabetes mellitus and obesity - that often associate with low T. In particular, this is the case of ED, but not of HSD, that, therefore, should be considered a more genuine correlate of T deficiency in adulthood and aging (late-onset hypogonadism, LOH)., Objectives: The aim of this review is to scrutinize evidence from our and other studies on sexual effects of T replacement therapy (TRT) in LOH., Materials and Methods: We will use preclinical and clinical data coming from our and other laboratories and meta-analyses., Results: Intervention studies in clinical trials involving subjects with LOH, and their meta-analyses, indicate that TRT is able to ameliorate HSD, spontaneous erection and ED. However, the relative improvement of ED by TRT is marginal [2-3 points of International Index of Erectile Function-erectile function domain (IIEF-EFD)] and significantly smoothed in subjects with the aforementioned metabolic conditions. In LOH, positive effects of TRT on other domains of sexual activity, such as orgasm and sexual satisfaction, are also apparent in the different meta-analyses., Discussion and Conclusions: Hence, TRT is a reasonable treatment for restoring sexual drive in LOH, with some additional positive effects also on erection (spontaneous and sexual-related) and on orgasm. In contrast, preclinical and clinical studies indicate that T administration to eugonadal subjects does not improve male sexual activity., (© 2020 American Society of Andrology and European Academy of Andrology.)

Competing Interests: None

Metabolic syndrome (MetS) clusters cardiovascular and metabolic risk factors along with hypogonadism and erectile dysfunction. Lifestyle modifications including physical exercise (PhyEx) are well-known treatments for this condition. In this study, we analyzed the effect of PhyEx on hypothalamic-pituitary-testis axis and erectile function by use of an animal MetS model, previously established in rabbits fed a high-fat diet (HFD). Rabbits fed a regular diet (RD) were used as controls. A subset of both groups was trained on a treadmill. HFD rabbits showed typical MetS features, including HG (reduced T and LH) and impairment of erectile function. PhyEx in HFD rabbits completely restored plasma T and LH and the penile alterations. At testicular and hypothalamic levels, an HFD-induced inflammatory status was accompanied by reduced T synthesis and gonadotropin-releasing hormone (GnRH) immunopositivity, respectively. In the testis, PhyEx normalized HFD-related macrophage infiltration and increased the expression of steroidogenic enzymes and T synthesis. In the hypothalamus, PhyEx normalized HFD-induced gene expression changes related to inflammation and glucose metabolism, restored GnRH expression, particularly doubling mRNA levels, and regulated expression of molecules related to GnRH release (kisspeptin, dynorphin). Concerning MetS components, PhyEx significantly reduced circulating cholesterol and visceral fat. In multivariate analyses, cholesterol levels resulted as the main factor associated with MetS-related alterations in penile, testicular, and hypothalamic districts. In conclusion, our results show that PhyEx may rescue erectile function, exert anti-inflammatory effects on hypothalamus and testis, and increase LH levels and T production, thus supporting a primary role for lifestyle modification to combat MetS-associated hypogonadism and erectile dysfunction.

The etiology of metabolic syndrome (MetS) is complex and involves the interplay between environmental, lifestyle and genetic determinants. MetS in men can be associated with a biochemical pattern of partial hypogonadotropic hypogonadism (HH). A similar pattern has been noted in both men and women with a variety of acute illnesses and chronic diseases, and there is ongoing debate regarding whether this phenomenon might adaptive (e.g. diverting resources from reproduction into survival), or maladaptive (e.g. anemia, sarcopenia, osteopenia and fatigue of androgen-deficiency amplify and widen the adverse consequences of the original disease-trigger). In women with hypothalamic amenorrhea (HA-HH secondary to chronic bioenergetic deficit from dietary restriction and/or intensive exercise), a genetic link to congenital HH (CHH) was recently established; women carrying monoallelic CHH gene mutations will typically not develop CHH, but are significantly more susceptible to HA. However, the male reproductive axis seems to be more resistant to similar environmental insults. In contrast, MetS-associated HH (mHH) is specifically a male phenomenon; the reproductive phenotype of females with MetS tending instead towards hyperandrogenism, rather than hypogonadism. The underlying pathogenic mechanisms responsible for mHH have not been clearly identified and, as yet, there has been no investigation of a potential role for CHH mutation carriage in its etiology. Over the decades, the use of either genetic- or diet-induced obesity and/or MetS animal models has greatly helped to illuminate the complex etiology of metabolic dysregulation, but the strong relationship between obesity/MetS and mHH in males has been largely neglected, with little or no information about the regulation of reproductive function by metabolic factors under conditions of bioenergetic excess. However, the pathogenic link between MetS and HH in males has been recently investigated in an animal model of high fat diet (HFD)-induced MetS, which perfectly recapitulates the human phenotype. Interesting insights derived by these studies have added novel information about the causative role played by hypothalamic alterations driven by metabolic disturbances in mHH. In particular, it appears that HFD-induced inflammatory injury at the hypothalamic level negatively affects GnRH neuron content, with the reduction of circulating gonadotropins and sex hormones being related to MetS severity.

Objective: The role of testosterone (T) in regulating body composition is conflicting. Thus, our goal is to meta-analyse the effects of T supplementation (TS) on body composition and metabolic outcomes., Methods: All randomized controlled trials (RCTs) comparing the effect of TS on different endpoints were considered., Results: Overall, 59 trials were included in the study enrolling 3029 and 2049 patients in TS and control groups respectively. TS was associated with any significant modification in body weight, waist circumference and BMI. Conversely, TS was associated with a significant reduction in fat and with an increase in lean mass as well as with a reduction of fasting glycaemia and insulin resistance. The effect on fasting glycaemia was even higher in younger individuals and in those with metabolic diseases. When only RCTs enrolling hypogonadal (total T <12  mol/l) subjects were considered, a reduction of total cholesterol as well as triglyceride (TGs) levels were also detected. Conversely, an improvement in HDL cholesterol levels as well as in both systolic and diastolic blood pressure was not observed., Conclusion: Our data suggest that TS is able to improve body composition and glycometabolic profile particularly in younger subjects and in those with metabolic disturbances. Specifically designed studies are urgently needed to confirm this point., (© 2016 European Society of Endocrinology.)

Delayed puberty (DP) in boys is the lack of sexual maturation at a chronological age of 14 years. Several conditions induce DP and they can be classified into reversible and irreversible causes. The most common cause of DP is constitutional delay of puberty (CDP; 63%), followed by DPs due to functional hypogonadotropic hypogonadism (HH; 20%), congenital isolated HH (9%) and hypergonadotropic hypogonadism (7%). A correct diagnosis, although often difficult, is pivotal for choosing the most adequate therapy. In CDP boys, expectant management can be an option. However, patient's psychological distress can be attenuated by short-term low-dose testosterone therapy, which can induce male secondary sexual characteristics. When therapy is discontinued in CDP, pubertal development continues similarly to normal boys. Long-term testosterone therapy is the only option in boys with DP due to hypergonadotropic hypogonadism, whereas in subjects with HH, besides long-term testosterone, also gonadotropins and gonadotropin-releasing hormone (GnRH) can be used. Gonadotropins and GnRH, besides inducing secondary sexual characteristics, can also induce testicular maturation and spermatogenesis. Other molecules, such as kisspeptin and neurokinin B agonists, are now under evaluation as new therapeutic options for treating DP., (© 2016 S. Karger AG, Basel.)

There is evidence demonstrating that sexual complaints represent the most specific symptoms associated with late onset hypogonadism, while central obesity is the most specific sign. In obese men, hypogonadism can further worsen the metabolic profile and increase abdominal fat. In addition, although hypogonadism can exacerbate obesity-associated erectile dysfunction (ED), recent data suggest that a direct contribution of fat-derived factors could be hypothesized. In particular, an animal model recently documented that fat accumulation induces several hepatic pro-inflammatory genes closely linked to corpora cavernosa endothelial dysfunction. Lifestyle modifications and weight loss are the first steps in the treatment of ED patients with obesity or metabolic diseases. In symptomatic hypogonadal men with metabolic impairment and obesity, combining the effect of testosterone substitution with lifestyle modifications could result in better outcomes.

Introduction: The relationship between serum prostate-specific antigen (PSA) and testosterone (T) levels is still controversial. According to the "saturation hypothesis," a significant relationship is apparent only in the low T range., Aim: To verify whether, in a large sample of male subjects seeking medical care for sexual dysfunction (SD), PSA might represent a reliable marker of T levels., Methods: A consecutive series of 3,156 patients attending our unit for SD was studied. Among them, only subjects without history of prostate disease and with PSA levels<4 ng/mL (N=2,967) were analyzed., Main Outcome Measures: Several hormonal and biochemical parameters were studied, along with structured interview on erectile dysfunction (SIEDY), ANDROTEST, and PsychoANDROTEST., Results: Receiver operating characteristic curve analysis for predicting severe hypogonadism (T<8 nmol/L) showed an accuracy of PSA=0.612±0.022 (P<0.0001), with the best sensitivity and specificity at PSA<0.65 ng/mL (65.2% and 55.5%, respectively). In the entire cohort, 254 subjects (8.6%) showed T<8 nmol/L and, among them, more than half (N=141, 4.8%) had PSA<0.65 ng/mL. After adjusting for age, low PSA was associated with hypogonadism-related features (i.e., delayed puberty, lower testis volume) and associated conditions, such as metabolic syndrome (hazard ratio [HR]=1.506 [1.241-1.827]; P<0.0001), type 2 diabetes (HR=2.044 [1.675-2.494]; P<0.0001), and cardiovascular diseases (HR=1.275 [1.006-1.617]; P=0.045). Furthermore, low PSA was associated with impaired sex- and sleep-related erections. The association between low PSA and hypogonadal symptoms and signs as well as with metabolic syndrome was retained even after adjusting for T levels. Sensitivity and positive predictive values of low PSA increased, whereas specificity and negative predictive value decreased as a function of age., Conclusions: PSA is a marker of T concentrations and it may represent a new tool in confirming hypogonadism. The determination of PSA levels might give insights not only on the circulating levels of total T but also on its active fractions., (© 2013 International Society for Sexual Medicine.)

Metabolic syndrome (MetS) is a diagnostic category which identifies subjects at high risk for diabetes and cardiovascular diseases, erectile dysfunction (ED) and male hypogonadism. However, MetS impact on male infertility has been poorly studied. We systematically evaluated possible associations between MetS and clinical characteristics in men with couple infertility. Out of 367 consecutive subjects, 351 men without genetic abnormalities were studied. MetS was defined according to the International Diabetes Federation&American Heart Association/National Heart,Lung, and Blood Institute classification. All men underwent physical, hormonal, seminal and scrotal ultrasound evaluation. Erectile and ejaculatory functions were assessed by International Index of Erectile Function-15 erectile function domain (IIEF-15-EFD) and Premature Ejaculation Diagnostic Tool (PEDT), respectively, while psychological symptoms by Middlesex Hospital Questionnaire. Out of 351 patients, 27 (7.7%) fulfilled MetS criteria. Among ultrasound features, in an age-adjusted logistic model, only testis inhomogeneity was significantly associated with increasing MetS factors (HR = 1.36 [1.09-1.70]; p < 0.01). In an age-adjusted model, MetS was associated with a stepwise decline in total testosterone (TT) (B = -1.25 ± 0.33; p < 0.0001), without a concomitant rise in gonadotropins. At univariate analysis, progressive motility and normal morphology were negatively related to the number of MetS components (both p < 0.0001), but when age and TT were introduced in a multivariate model, only sperm morphology retained a significant association (B = -1.418 ± 0.42; p = 0.001). The risk of ED (IIEF-15-EFD score <26) increased as a function of the number of MetS factors, even after adjusting for age and TT (HR = 1.45[1.08-1.95]; p < 0.02). No association between PEDT score and MetS was observed. Finally, after adjusting for age and TT, somatization and depressive symptoms were associated with increasing MetS components (B = 0.66 ± 0.03, p < 0.05; B = 0.69 ± 0.03, p < 0.02; respectively). In conclusion, in men with couple infertility, MetS is associated with hypogonadism, poor sperm morphology, testis ultrasound inhomogeneity, ED, somatization and depression. Recognizing MetS could help patients to improve not only fertility but also sexual and overall health., (© 2013 American Society of Andrology and European Academy of Andrology.)

In the male, metabolic syndrome (MetS) is associated to an increased risk of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). A recently established rabbit model of high fat diet (HFD)-induced MetS showed hypogonadism and the presence of prostate gland alterations, including inflammation, hypoxia and fibrosis. The present study investigated whether HFD-induced MetS might also alter bladder structure and function. Testosterone and the farnesoid X receptor (FXR) agonist INT-747, were evaluated for possible effects on HFD bladder. MetS rabbits develop bladder alterations, including fibrosis (reduced muscle/fiber ratio), hypoxia [2-fold increase as compared to regular diet (RD) group], low-grade inflammation (increased leukocyte infiltration and inflammatory markers) and RhoA/ROCK hyperactivity. Bladder strips from HFD rabbits, pre-contracted with carbachol, showed an overactive response to the selective ROCK inhibitor Y-27632. All these HFD-induced bladder alterations were partially blunted by testosterone and almost completely reverted by INT-747. Both treatments prevented some MetS features (glucose intolerance and visceral fat increase), thus suggesting that their effects on bladder could be ascribed to an improvement of the metabolic and/or hypogonadal state. However, a pathogenetic role for hypogonadism has been ruled out as GnRH analog-induced hypogonadal rabbits, fed a regular diet, did not show any detectable bladder alterations. In addition, INT-747 did not revert the MetS-induced hypogonadal state. FXR mRNA was highly expressed in rabbit bladder and positively associated with visceral fat increase. A direct effect of INT-747 on bladder smooth muscle was further suggested by inhibition of RhoA/ROCK-mediated activity by in vitro experiments on isolated cells. In conclusion, HFD-related MetS features are associated to bladder derangements, which are ameliorated by testosterone or INT-747 administration. INT-747 showed the most marked effects in counteracting MetS-related RhoA/ROCK overactivity, thus opening novel therapeutic opportunities for this drug., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Since the phenotype and clinical need of the hypogonadal individuals changes dramatically over time, versatile therapies are needed., Areas Covered: The authors review the available evidence on possible therapies., Expert Opinion: In the case of primary hypogonadism starting early in life, substitution with testosterone (T) is the only choice. For secondary congenital hypogonadism, we recommend starting with gonadotrophins to allow the testes to reach pubertal size. Thereafter, T replacement therapy can be administered until fertility is desired. At that time, gonadotrophins should be employed until fathering occurs. Antiestrogens are an alternative, however, their efficacy has not been adequately tested. In the presence of increased estrogen production symptoms (breast tenderness and gynecomastia), a short-term trial with non-aromatizable androgens (dihydrotestosterone mesterolone or oxandrolone) could be advisable. However, after a few months of therapy, switching to other aromatizable preparations is recommended, to prevent bone loss. When prostate safety is concerned, the use of steroidal or non-steroidal selective androgen receptor modulators that are less susceptible to 5α reduction might be advisable. An attractive possibility is the combined use of testosterone with 5α inhibitors. Theoretically, also estrogen receptor-beta ligands could be employed, however the development of these compounds, although promising, is still in its infancy.

Late-onset hypogonadism (LOH) has been considered the most common form of male hypogonadism with a prevalence of approximately 1 in 100 men. Diagnosis of LOH should be made in symptomatic men with unequivocally low serum testosterone (T) levels. However, its clinical presentation is often insidious and difficult to recognize because it is characterized by nonspecific symptoms that make differential diagnosis with physiological ageing problematic. Sexual dysfunction is the most important determinant for medical consultation and the most specific symptom associated with low T. We therefore analysed a consecutive series of 1734 subjects who attended our unit for sexual dysfunction to investigate the associations between low T (different thresholds), sexual parameters, medical history data (delayed puberty, pituitary disease or cryptorchidism) and their physical exam results. Metabolic parameters, in particular waist circumference, display the greatest accuracy in detecting low T. We found that only the association of several symptoms and signs could significantly raise the clinical suspicion of low T. Structured inventories, which cluster together symptoms and signs of hypogonadism, can help clinicians suspect androgen deficiency. In particular, structured interviews, such as ANDROTEST, have been demonstrated to have a greater accuracy when compared to self reported questionnaires in detecting low T levels.

Background: The relationship between metabolic syndrome (MetS), male hypogonadism and their possible interaction in cardiovascular (CV) risk stratification are not completely understood., Aim: We reviewed relationships between testosterone (T) and MetS emphasizing their possible interaction in the pathogenesis of CV diseases., Materials and Methods: A systematic search of published evidence was performed using Medline (1969 to January 2011)., Results: Cross-sectional data have shown that subjects with MetS have lower levels of total T (TT) (about 3 nmol/l), as hypogonadism is more evident in subjects with than in those without erectile dysfunction (ED) than in those without. Longitudinal evidence shows that low T is allocated with a higher risk of subsequent development of MetS, although the reverse condition is also possible. Which are the factors in MetS responsible for the low T is not completely clarified. In clinical studies, increased waist circumference is the major determinant of MetS-associated hypogonadism. Our experiments in rabbits do not support the idea that visceral fat is the main determinant of MetS-associated male hypogonadism. Only few randomized clinical trials have evaluated the impact of T replacement therapy (TRT) in patients with MetS. Available evidence suggests that TRT decreases visceral fat accumulation and ameliorates insulin sensitivity, whereas androgen deprivation increases abdominal adiposity., Conclusions: The clinical significance of the MetS-associated hypogonadism needs further clarifications. In particular, it has not been completely clarified if low T might be considered a cause or a consequence of MetS. The benefit of TRT in term of the reduction of CV risk needs to be confirmed in larger and longer studies.

Introduction: We have previously demonstrated that oxytocin (OT) and endothelin-1 (ET-1) peripherally regulate epididymal motility in an estrogen-dependent way. Because RhoA/Rho-kinase (ROCK) pathway is a contractile effector downstream to both OT and ET-1 receptors, we hypothesized an estrogenic modulation of OT- and ET-1-induced contraction through the up-regulation of RhoA/ROCK signaling., Aim: To evaluate the effect of changing endocrine milieu on RhoA/ROCK pathway in the epididymis., Methods: We induced a pharmacological hypogonadotropic hypogonadism in rabbits and replaced hypogonadal animals with different sex steroids (testosterone, T, or estradiol valerate, [E(2v)]). Effects of estrogen deprivation were also evaluated in rabbits chronically treated with the P450-aromatase inhibitor letrozole. An "in vitro" model of human epididymal smooth muscle cells was established and stimulated with sex hormones (72 hours). Protein and mRNA expression and functional activity of RhoA/ROCK signaling were studied by quantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, western blot analysis, cell migration and by "in vitro" contractility studies using the ROCK inhibitor Y-27632., Main Outcome Measures: Effects of sex steroids on expression and functional activation of RhoA/ROCK signaling in rabbit epididymis and human epididymal smooth muscle cells., Results: The relaxant effect of Y-27632 on ET-1-pre-contracted epididymal strips was significantly reduced in hypogonadal rabbits, as well as in letrozole-treated animals. T supplementation normalized T plasma levels, but not Y-27632 epididymal strip sensitivity. E(2)v not only completely restored Y-27632 responsiveness but even amplified it, indicating an estrogenic up-regulation of RhoA/ROCK pathway. Accordingly, ROCK1 protein and gene expressions were strongly induced by E(2)v but not by T. The estrogen-induced up-regulation of RhoA/ROCK signaling was confirmed in human epididymal smooth muscle cells., Conclusions: Our results suggest that estrogens regulate epididymal motility by increasing RhoA/ROCK signaling, and therefore calcium sensitivity, which tunes up responsiveness to contractile factors.

Background: Most men following radical retropubic prostatectomy (RRP) are afflicted by erectile dysfunction (ED). RRP-related ED occurs as a result of surgically elicited neuropraxia, leading to histological changes in the penis, including collagenization of smooth muscle and endothelial damage., Aim: To verify whether hypogonadism could contribute to the pathogenesis of RRP-ED., Methods: Effects of testosterone (T), alone or in association with long-term tadalafil (Tad) treatment in a rat model of bilateral cavernous neurotomy (BCN)., Main Outcome Measures: Penile tissues from rats were harvested for vasoreactivity studies 3 months post-BCN. Penile oxygenation was evaluated by hypoxyprobe immunostaining. Phosphodiesterase type 5 (PDE5), endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) mRNA expression were quantified by Real Time quantitative reverse transcription polymerase chain reaction (qRT-PCR)., Results: In BCN rats, we observed the onset of an overt condition of hypogonadism, characterized by reduced T plasma level, reduced ventral prostate weight, reduced testis function (including testis weight and number of Leydig cells), with an inadequate compensatory increase of luteinizing hormone. BCN induced massive penile hypoxia, decreased muscle/fiber ratio, nNOS, eNOS, PDE5 expression, increased sensitivity to the nitric oxide donor, sodium nitroprusside (SNP), and reduced the relaxant response to acetylcholine (Ach), as well as unresponsiveness to acute Tad dosing. In BCN rats, chronic Tad-administration normalizes penile oxygenation, smooth muscle loss, PDE5 expression, SNP sensitivity, and the responsiveness to the acute Tad administration. Chronic Tad treatment was ineffective in counteracting the reduction of nNOS and eNOS expression, along with Ach responsiveness. T supplementation, in combination with Tad, reverted some of the aforementioned alterations, restoring smooth muscle content, eNOS expression, as well as the relaxant response of penile strips to Ach, but not nNOS expression., Conclusion: BCN was associated with hypogonadism, probably of central origin. T supplementation in hypogonadal BCN rats ameliorates some aspects of BCN-induced ED, including collagenization of penile smooth muscle and endothelial dysfunction, except surgically induced altered nNOS expression.

According to all the consensus and statements of the major societies, hypogonadism should be considered a medical problem, termed late onset hypogonadism (LOH) or testosterone deficiency syndrome (TDS), only when symptoms are present. One of the most common symptoms of LOH/TDS is sexual dysfunction (SD). The main purpose of this review is to discuss the role of testosterone (T) in men's sexual function, including epidemiology, pathophysiology, diagnostic procedures, and treatment efficacy in patients affected by erectile dysfunction (ED). The prevalence of hypogonadism in men with ED ranges from 1.7% to 35%. In ED patients, hypogonadism is often associated with reduced sexual desire and nocturnal penile erections, while association with sex-induced erection is less evident. This is because T regulates not only cyclic guanosine monophosphate (cGMP) formation, through nitric oxide synthase (NOS) stimulation, but also its catabolism, through phosphodiesterase-5 (PDE5) activity. The androgen-dependent PDE5 expression could explain the reduced effectiveness of PDE5 inhibitors (PDE5i) in the treatment of erectile dysfunction in hypogonadal patients. Accordingly, T substitution in these subjects restores responsiveness to PDE5i. Recognising hypogonadism in patients with ED is essential in order to appropriately treat the disease. However, suspecting LOH/TDS in SD patients is not an easy task. Recently published structured inventories, such as ANDROTEST, might help physicians to recognize hypogonadism and to further pursue its appropriate diagnosis and treatment.

Obesity and male hypogonadism (HG) are often associated, as demonstrated in all cross-sectional studies. Prospective studies have indicated that i) having HG at baseline increases the risk of visceral obesity (and metabolic syndrome) and that ii) obesity induces incident HG. Hence, there is a bidirectional relationship between the two conditions. This is the main topic of this review, along with some pathogenic considerations. Meta-analysis of intervention studies indicates that treating obesity is a very efficient treatment for obesity-induced HG. The mechanism by which obesity induces HG has not yet been completely understood, but dietary-induced hypothalamic inflammation, along with a decreased GnRH release, is plausible. Among patients seeking medical care for obesity, the proportion of HG is relatively high. The prevalence of obesity among patients referring for sexual dysfunction is also elevated. Hence, in symptomatic, obese, hypogonadal subjects, testosterone supplementation (TS) can be considered. Whereas long-term uncontrolled register studies suggest that TS could decrease weight, analysis of controlled studies only support a parallel increase in lean mass and decrease in fat mass, with a resulting null effect on weight. Considering that T induces an increase in muscle mass, it is conceivable that the amount of activity obese people can undertake after TS will increase, allowing a closer adherence to physical exercise programs. Some studies, here meta-analyzed, support this concept. [ABSTRACT FROM AUTHOR]

The most important pathway underlying the penile erection is the nonadrenergic/noncholinergic signalling, which through the release of nitric oxide (NO), leads to an intracellular increase of cyclic GMP (cGMP), the main secondary messenger mediating tumescence in the penis. Interestingly, both cGMP formation and degradation are affected by testosterone (T). In fact, beyond the well-known role of T in regulating sexual desire and NO release, recent experimental evidences from our group showed that T also regulates the expression of phosphodiesterase type 5 (PDE5), the hydrolytic enzyme involved in cGMP breakdown. This antithetic role of T seems to be the main way through which the peripheral hormonal regulation of penile erections occurs, allowing an important synchronization between erectile processes and sexual desire. Hence, erections are still possible in hypogonadal conditions where a decreased cGMP formation, because of impaired NO production, is counterbalanced by a reduced cGMP hydrolysis. The purpose of this review is to describe evidences about the peripheral role of T in regulating penile erection and to justify the importance to test T plasma levels in those patients with erectile dysfunction who do not respond to PDE5 inhibitors. [ABSTRACT FROM AUTHOR]

Exercise and physical activity are recommended for either primary management or prevention of Metabolic syndrome (MetS), a cluster of metabolic and cardiovascular risk factors often associated to hypogonadism in men. PAS-staining fiber typing in SkM cross-sections confirmed a shift from type-I to type-II fibers in HFD, which was normalized by T. Moreover, T significantly increased the expression of both myogenic and muscle metabolism (insulin-dependent signaling, lipid turnover) markers. Conclusions Our results indicate that T could be useful to promote oxidative muscle metabolism altered by MetS, thus improving exercise performance. [Extracted from the article]