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Skeletal muscle atrophy is a hallmark of severe spinal cord injury (SCI) that is precipitated by the neural insult and paralysis. Additionally, other factors may influence muscle loss, including systemic inflammation, low testosterone, low insulin-like growth factor (IGF)-1, and high-dose glucocorticoid treatment. The signaling cascades that drive SCI-induced muscle loss are common among most forms of disuse atrophy and include ubiquitin-proteasome signaling and others. However, differing magnitudes and patterns of atrophic signals exist after SCI versus other disuse conditions and are accompanied by endogenous inhibition of IGF-1/PI3K/Akt signaling, which combine to produce exceedingly rapid atrophy. Several well-established anabolic agents, including androgens and myostatin inhibitors, display diminished ability to prevent SCI-induced atrophy, while ursolic acid and β2-agonists more effectively attenuate muscle loss. Strategies combining physical rehabilitation regimens to reload the paralyzed limbs with drugs targeting the underlying molecular pathways hold the greatest potential to improve muscle recovery after severe SCI. [ABSTRACT FROM AUTHOR]

Previous research has shown a decrease in serum testosterone levels in male patients with depression. In recent years, the results of testosterone replacement therapy (TRT) to improve depression have been mixed. Using the classic CUMS model, we induced depressive-like behaviors in rats and observed a decrease in their serum testosterone levels along with an increase in androgen receptor expression in the hippocampus. We then performed castration and sham surgery on male rats and found that testosterone deprivation led to the manifestation of depressive-like behavior that could be ameliorated by TRT. Through a repeated measures experiment consisting of five blocks over a period of 25 days, we discovered that the reduction in depressive-like behavior in testosterone-deprived rats began 22 days after drug administration (0.5 and 0.25 mg/rat). Furthermore, rats in 0.5mgT group showed the most significant improvements. Subsequently, this dose was used in CUMS rats and reduced the occurrence of depressive-like behaviors. Our study has demonstrated the complex interplay between depression and testosterone, as well as the intricate dose-response relationship between TRT and reduction in depression. Our research supports the use of TRT to alleviate depression, but dosage and duration of treatment are critical factors in determining efficacy. • Serum testosterone levels decrease in rats with depressive-like behaviors, accompanied by an increase in AR expression. • Male rats subjected to testosterone deprivation exhibit depressive-like behavior. • A dosage of 0.5 mg/rat is most effective in alleviating depressive-like behavior, followed by lower dosage (0.25 mg/rat). • Duration of treatment and dosage are critical factors in the efficacy of TRT in alleviating depression. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the association between testosterone replacement therapy (TRT) in prostate cancer (CaP) patients who underwent definitive local therapy with curative intent with biochemical recurrence (BCR).Materials and Methods: A literature search using PubMed, Scopus, Web of Science, and Cochrane Library was conducted on November 2018 to identify relevant studies according to the Preferred Reporting Items for Systematic Review and Meta Analysis guidelines. The pooled BCR rate in CaP men treated with TRT after definitive local therapy with curative intent was calculated using a random effects model.Results: Twenty-one studies were eligible. The overall pooled BCR rate was 0.01 (95%CI 0.00-0.02) suggesting a lack of association between TRT and BCR; there was no heterogeneity among included studies (I2 = 24.34%, P = 0.15). In subgroup analyses, pooled BCR rates were 0.00 (95%CI 0.00-0.02) in patients treated with radical prostatectomy and 0.02 (95%CI 0.00-0.04) in patients treated with external beam radiation therapy, brachytherapy, cryotherapy, or high intensity focused ultrasound; there was no heterogeneity in the subgroup analyses (I2 = 19.88%, P = 0.18).Conclusions: In this systematic review and meta-analysis, we did not observe higher rate of BCR after TRT for nonmetastatic CaP patients after definitive local therapy. Based on these data, others and we have outlined a phase I/II trial assessing the safety and benefits of TRT in select men with secondary symptomatic hypogonadism who have no active disease after definitive local CaP therapy with curative intent. [ABSTRACT FROM AUTHOR]

Both obesity and orchiectomy lead to the development of brain pathologies and cognitive decline. Testosterone replacement therapy (2 mg/kg/day TRT) and dipeptidyl peptidase-4 inhibitor (vildagliptin) improved cognition in orchiectomized rats, and obese rats. However, both had no beneficial effects in brain of orchiectomized-obese rats. TRT (>2 mg/kg/day) is possible to attenuate brain defects in those rats, but high dose of TRT causes adverse effects. Then, combined effect of low-dose TRT (1 mg/kg/day) and vildagliptin on brain and cognitive functions in orchiectomized-obese rats should be investigated. Sixty male rats were fed with either a normal diet (ND) or a high-fat diet (HFD) for 28 weeks. At week 13, both ND and HFD-fed rats had either a sham-operation or an orchiectomy. At week 25, orchiectomized rats were treated with either: a vehicle, 2 mg/kg/day TRT, vildagliptin (3 mg/kg/day) or a combined vildagliptin with 1 mg/kg/day TRT for 4 weeks. Then, metabolic parameters, brain and cognitive functions were determined. Hippocampal oxidative stress, apoptosis, dendritic spine loss, microglial hyperactivity, and cognitive decline were found in orchiectomized ND-fed rats and sham-operated HFD-fed rats. Interestingly, orchiectomy aggravated these brain pathologies and cognitive decline in HFD-fed rats. In orchiectomized ND-fed rats, all treatments restored brain and cognitive functions. In orchiectomized HFD-fed rats, monotherapies ameliorated these brain pathologies, while the combined therapies had the greatest beneficial effect on the brains. These findings suggest the combined therapies may be the best therapeutic approach for restoring brain functions in the orchiectomized-obese condition. • Both testosterone deprivation and obese condition caused cognitive impairment. • Testosterone deprivation aggravated cognitive decline in obese condition. • Vildagliptin and TRT improved cognitive function in orchiectomized HFD-fed rats. • Combined therapies had the greatest beneficial effect in orchiectomized HFD-fed rats. [ABSTRACT FROM AUTHOR]

The finding of low circulating testosterone level in men is relatively frequent. The symptoms of hypogonadism are very frequent in the aging men. However, the diagnosis of hypogonadism is often neglected and the opportunity to replace low testosterone in older men is highly debated. The aim of this narrative review is to summarize the steps necessary to formulate a proper diagnosis and to guide toward an individualized treatment. While universally recognized the need to treat the young adults with known causes of pituitary or testicular failure, there are controversies on the cost-benefit of treating testosterone deficiency in older men. Discrepancies among the several available guidelines do not help to clarify the scenario, however, the recent larger clinical trials have shed some light on the fact that testosterone treatment carries some benefit, that is not free from risks. We provide an updated review of the diagnostic hallmarks, the several treatment modalities, with their advantages and disadvantages, and how to individualize and monitor treatment in order to maximize the benefits and minimize the risks. The treatment of male hypogonadism can no longer be downgraded and must become part of the cultural baggage of the endocrinologist. [ABSTRACT FROM AUTHOR]

Male hypogonadism is associated with reduced quality of life and the development of co-morbidities including obesity, diabetes mellitus, and dyslipidaemia. The mainstay of treatment for male hypogonadism is testosterone replacement therapy (TRT). However, TRT has recognised side effects including impaired spermatogenesis and there are concerns regarding its use in men with concurrent cardiovascular disease. Thus, there has been an impetus to develop novel androgen therapies for treating male hypogonadism to mitigate the side effects of TRT. This review will discuss the benefits and adverse effects of TRT, and novel therapies including nasal testosterone, aromatase inhibitors, selective oestrogen receptor modulators, and selective androgen receptor modulators. [ABSTRACT FROM AUTHOR]

Testosterone supplementation therapy (TST) is a longstanding treatment for hypogonadal men with type 2 diabetes mellitus (T2DM), even though the benefits of TST are variable among trials. This meta-analysis was done to determine the specific role of TST in hypogonadal men with T2DM. PubMed, Embase, and Google Scholar were queried to discover eligible randomized controlled trials (RCTs) and observational studies. To quantify the specific effects of TST, we estimated pooled mean differences (MDs) and relative risks with 95% confidence intervals (CIs). Our meta-analysis included 1596 hypogonadal T2DM subjects from 12 randomized controlled trials and one observational study. TST can significantly enhance glycemic control compared to placebo by decreasing homeostatic model assessment of insulin resistance (WMD = −1.55 [-2.65, −0.45]; p = 0.26; I2 = 20.2%), fasting glucose (WMD = −0.35 [-0.79, 0.10]; p = 0.07; I2 = 69.7%), fasting insulin (WMD = −2.88 [-6.12, 0.36]; p = In addition, TST can decrease cholesterol (WMD = −0.28 [-0.47, −0.09] p = 0.0008; I2 = 91%) and triglyceride (WMD = −0.23 [-0.43, −0.03] p = 0.03; I2 = 79.2%). Furthermore, Testosterone therapy is related to a significant rise in total testosterone levels (WMD = 5.08 [2.90, 7.26] p = 0.0002; I2 = 92.9%). Pooling of free testosterone levels indicated a larger increase in the patients who got TST than placebo (WMD = 81.21 [23.87, 138.54] p = 0.07; I2 = 70%). Our findings suggested that TST can enhance glycemic control and hormone levels and reduce total cholesterol, triglyceride, LDL cholesterol whereas increase HDL cholesterol in hypogonadal T2DM patients. Therefore, in these patients, we propose TST alongside anti-diabetic treatment. • Testosterone supplementation therapy (TST) has been used to treat hypogonadal men with type 2 diabetes mellitus (T2DM) for a long time.. • TST decreases homeostatic model assessments of insulin resistance, HbA1c, fasting glucose, and fasting insulin.. • TST can significantly decrease total cholesterol and triglyceride levels. [ABSTRACT FROM AUTHOR]

Objective To determine the effect of enclomiphene citrate in men with secondary hypogonadism. Design Phase II clinical trial. Setting Community dwelling men making visits to physician offices. Patient(s) Men with secondary hypogonadism. Intervention(s) Oral administration of enclomiphene citrate or 1% topical T gel. Main Outcome Measure(s) Luteinizing hormone, FSH, T, and semen analysis. Result(s) Treatment with enclomiphene citrate resulted in increased morning serum T, E 2 , and LH levels similar to those obtained with a topical T gel in men with secondary hypogonadism. Follicle-stimulating hormone and LH were increased with enclomiphene, and sperm counts were conserved. Conclusion(s) Enclomiphene citrate reverses the two hallmarks of secondary hypogonadism, namely, low serum total T and low or inappropriately normal LH while preserving sperm production. Clinical Trial Registration Number NCT01270841 ( ClinicalTrials.gov Identifier NCT01270841 ). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To analyze how frequently and why men presenting with infertility take testosterone (T) and if negative effects of T on semen parameters are reversed following cessation. Design: Analysis of a prospectively collected database. Setting: Male Infertility clinic. Patient(s): Men presenting for fertility evaluation from 2008 to 2012. Intervention(s): None. Main Outcome Measure(s): The frequency and reason for T use in the infertile male population, and semen and hormonal parameters while on T and following discontinuation. Result(s): A total of 59/4,400 men (1.3%) reported taking T. T was prescribed by a variety of physicians, including endocrinologists (24%), general practitioners (17%), urologists (15%), gynecologists (5%), and reproductive endocrinologists (3%). Only one of the men admitted that he had obtained T from an illicit source. More than 82% of men were prescribed T for the treatment of hypogonadism, but surprisingly, 12% (7/59) were prescribed T to treat their infertility. While on T, 88.4% of men were azoospermic, but by 6 months after T cessation, 65% of the men without other known causes for azoospermia recovered spermatogenesis. Conclusion(s): In Canada, T was not commonly used by men presenting for fertility investigation (1.3%). Close to 2/3 of infertile men using T recovered spermatogenesis within 6 months of T discontinuation. [ABSTRACT FROM AUTHOR]

Late-onset hypogonadism (LOH) is a relatively common conditions affecting the aging male. The aim of this review is to summarize the available evidence regarding LOH and its interaction with general health. LOH is often comorbid to obesity and several chronic diseases. For this reason lifestyle modifications should be strongly encouraged in LOH subjects with obesity, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) and good treatment balance of chronic diseases. Medical therapy of LOH should be individualized depending on the etiology of the disease and the patient's expectations. Available evidence seems to suggest that testosterone replacement therapy is able to improve central obesity (subjects with MetS) and glycometabolic control (patients with MetS and T2DM), as well as to increase lean body mass (HIV, chronic obstructive pulmonary disease), along with insulin resistance (MetS) and peripheral oxygenation (chronic kidney diseases). However, it should be recognized that the number of studies on benefits of T supplementation is too limited to draw final conclusions. Longer and larger studies are needed to better clarify the role of TRT in such chronic conditions. [Copyright &y& Elsevier]

Androgens have been implicated in prostate tumourigenesis. However, no association between circulating levels of androgens and prostate cancer risk was found in a recent large pooled analysis of prospective studies. A decreased risk of prostate cancer among men treated with finasteride, a 5α-reductase inhibitor which reduces levels of dihydrotestosterone, was observed in the Prostate Cancer Prevention Trial (PCPT), a large clinical trial. In the PCPT, a higher number of high-grade tumours was found in the finasteride group than in the control group; the reason for this finding is still unclear. Treatment of symptoms of late-onset hypogonadism – such as decreased muscle and bone mass and decreased cognition and libido – has become more prevalent with the advent of new forms of administration of testosterone replacement therapy. One small placebo-controlled study showed no increase in incidence of prostate cancer after 6 months of testosterone therapy, but data on the safety of testosterone replacement therapy remain limited. [Copyright &y& Elsevier]

Abstract: Objective:: The aim of this work was to review thepharmacokinetic and clinical profile of Testim® (Auxilium Pharmaceuticals, Norristown, Pennsylvania) 1% gel formulation of testosterone for the treatment of male hypogonadism. Methods:: An English-language search of the medical literature was conducted using PubMed (1998–December 2004) and EMBASE (1998–December 2004). Search terms included ag(e)ing male, male hypogonadism, late-onset hypogonadism, testosterone, testosterone deficiency, testosterone therapy, testosterone replacement therapy, androgen therapy, testosterone gel, and Testim. Bibliographies of retrieved articles were also reviewed. Results:: Five published clinical studies were reviewed.Testim 50 mg showed clear pharmacokinetic differences from AndroGel® (known as Testogel® in Europe; Unimed Pharmaceuticals, Inc., and Solvay Pharmaceuticals, Inc., Marietta, Georgia) 1% testosterone gel 50 mg, with increases of 30% (90% CI, 8%–57%) and 47% (90% CI, 20%–79%) versus AndroGel, respectively, in AUC0–24h for total serum testosterone and free testosterone. In a 30-day study of 638 men with hypogonadism, sexual desire scores and sexual motivation scores increased after Testim treatment at weeks 1, 2, 3, and 4 (each, P < 0.001). During 12 months of treatment with Testim 50 or 100 mg in 371 men with hypogonadism, total serum testosterone levels were raised to and maintained within the normal adult range, lean body mass increased by 2.2 kg (P < 0.001), fat mass fell by 2.1% (P < 0.001), and bone mineral density increased by 2.58% (P < 0.001). Mean scores for sexual desire, performance, motivation, and spontaneous erections were all significantly higher (all, P < 0.001) than at baseline for all time points during 12-month studies of Testim. In 2 studies comparing Testim with different testosterone patches, treatment with the gel resulted in 10-fold fewer application-site reactions than either patch. Conclusions:: In men with hypogonadism, Testimgel raised and maintained serum testosterone levels to within the normal adult range, alleviated signs and symptoms associated with hypogonadism, and was well tolerated. [Copyright &y& Elsevier]

• Clinical trials have shown presence and absence of correlation between cardiovascular risks and testosterone therapy. • Such contradictions have reduced certainty in predicting cardiovascular risks during testosterone replacement therapy. • The cardiovascular risk of such therapy was found to be associated with age. • The risk was even more severe in patients who had a previous history of myocardial infarction or stroke. Since the male secondary sex characters, libido and fertility are attributed to their major androgen hormone testosterone, the sub-optimum levels of testosterone in young adults may cause infertility and irregularities in their sexual behaviour. Such deficiency is often secondary to maladies involving testes, pituitary or hypothalamus that could be treated with an administration of exogenous testosterone. In the last few decades, the number of testosterone prescriptions has markedly increased to treat sub-optimal serum levels even though its administration in such conditions is not yet approved. On account of its associated cardiovascular hazards, the food and drug authority in the United States has issued safety alerts on testosterone replacement therapy (TRT). Owing to a great degree of conflict among their findings, the published clinical trials seem struggling in presenting a decisive opinion on the matter. Hence, the clinicians remain uncertain about the possible cardiovascular adversities while prescribing TRT in hypogonadal men. The uncertainty escalates even further while prescribing such therapy in older men with a previous history of cardiovascular ailments. In the current review, we analysed the pre-clinical and clinical studies to evaluate the physiological impact of testosterone on cardiovascular and related parameters. We have enlisted studies on the association of cardiovascular health and endogenous testosterone levels with a comprehensive analysis of epidemiological studies, clinical trials, and meta-analyses on the cardiovascular risk of TRT. The review is aimed to assist clinicians in making smart decisions regarding TRT in their patients. [ABSTRACT FROM AUTHOR]

Objective: To investigate the multiparametric prostate magnetic resonance imaging (mpMRI) findings in patients treated with testosterone replacement therapy (TRT) while on active surveillance for low-risk prostate cancer.Methods: We retrospectively reviewed 12 patients who underwent mpMRI before and after TRT while on active surveillance. Changes in serum testosterone level, prostate-specific antigen (PSA), prostate biopsy findings, prostate volume, and Prostate Imaging Reporting and Data System Version 2 (PI-RADSv2) score before and after TRT were summarized.Results: After TRT, there was a significant increase in serum testosterone (516.5ng/dl vs. 203.0ng/dl), PSA (4.2ng/ml vs. 3.3ng/ml), and prostate volume (55.2cm3 vs. 39.4cm3). In total, 2 patients had biopsy progression during the study period. The PI-RADSv2 scores before and after TRT were unchanged in 10/12 patients; none of these demonstrated biopsy progression on post-TRT. The PI-RADSv2 scores increased after TRT in 2/12 patients; both showed Gleason score upgrade on follow-up biopsy. Of these 2 patients, 1 patient underwent radical treatment due to clinical progression. The area under the curve for detecting biopsy progression calculated from PI-RADSv2 score after TRT was 0.90, which was better than that calculated from post-TRT PSA level (0.48).Conclusions: After TRT, mpMRI findings remained stable in patients without biopsy progression, whereas PI-RADSv2 score increase was identified in patients with Gleason score upgrade on follow-up biopsy. [ABSTRACT FROM AUTHOR]