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INTRODUCTION: Testosterone replacement therapy (TRT) can improve quality of life for men with hypogonadism. However, it is generally avoided in patients with a history of prostate cancer or breast cancer as there is uncertainty about risks. This case illustrates an example of synchronous metastatic prostate cancer and male breast cancer following TRT. PRESENTATION OF CASE: A 72-year-old man with previously treated intermediate-risk prostate adenocarcinoma experienced a gradual rise in prostate-specific antigen (PSA) while self-administering testosterone replacement. He was later found to have recurrent metastatic prostate cancer and prior to initiating androgen deprivation therapy (ADT), he was also diagnosed with male breast cancer. His treatment has consisted of continued ADT for metastatic castration-sensitive prostate cancer (mCSPC) as well as surgical resection of his breast cancer. DISCUSSION: ADT plays a role in treatment of male breast cancer and prostate cancer. TRT remains relatively contraindicated in patients with a history of these malignancies, but the evidence supporting this recommendation is somewhat limited. CONCLUSION: This case highlights the potential risk for synchronous recurrent prostate and new male breast cancer following TRT. Further studies are needed to better elucidate the increased risks of these malignancies with TRT.

BackgroundHigh-dose testosterone replacement therapy (TRT), paired with finasteride (type II 5α-reductase inhibitor), improves body composition, muscle strength, and bone mineral density (BMD) in older men, without inducing prostate enlargement—a side effect associated with TRT. Men with spinal cord injury (SCI) exhibit neuromuscular impairment, muscle atrophy, bone loss, and increased central adiposity, along with low testosterone. However, sparse evidence supports TRT efficacy after SCI.MethodsThis parallel-group, double-blind, placebo-controlled, and randomized clinical trial (RCT) is a pilot study that enrolled men (N = 12) with low to low–normal testosterone and gait impairments after chronic motor-incomplete SCI. Participants received high-dose intramuscular TRT (testosterone-enanthate, 125 mg/week) with finasteride (5 mg/day) vs. vehicle+placebo for 12 months. Change relative to baseline was determined for body composition, musculoskeletal outcomes, and prostate size, with effect sizes calculated between groups using Hedges’ g. Adverse events and feasibility were assessed.ResultsTRT + finasteride consistently increased testosterone (g = 1.16–3.08) and estradiol (g = 0.43–3.48), while concomitantly reducing dihydrotestosterone (g = 0.31–2.27). Very large effect sizes at both 6 and 12 months suggest TRT + finasteride increased whole-body fat-free (lean) mass (+3–4% vs. baseline, g = 2.12–2.14) and knee extensor (KE) whole-muscle cross-sectional area (+8–11% vs. baseline, g = 2.06–2.53) more than vehicle+placebo. Moderate-to-large effect sizes suggest TRT + finasteride increased KE maximal voluntary isometric torque (+15–40% vs. baseline, g = 0.47–1.01) and femoral neck and distal femur BMD from 6 months onward (g = 0.51–1.13), compared with vehicle+placebo, and reduced fat mass 9–14% within the whole-body, trunk, and android (visceral) regions at 12 months (g = 0.77–1.27). TRT + finasteride also produced small effect sizes favoring lesser prostate growth than vehicle+placebo (g = 0.31–0.43). The participant retention, drug compliance, and incidence and severity of adverse events were similar among the groups.ConclusionThese data provide proof-of-concept and rationale for larger RCTs aimed at discerning the impact of TRT + finasteride on body composition, musculoskeletal health, and physical function in men with SCI, along with effect sizes and variance of responses to assist in planning subsequent trials.Clinical trial registrationClinicalTrials.gov, identifier NCT02248701.

Background Secondary analyses of the Testosterone Replacement Therapy for Assessment of Long-Term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial revealed significantly higher rates of new-onset atrial fibrillation (AF) and acute kidney injury (AKI) in the testosterone replacement therapy (TRT) cohort. Aim To validate the secondary findings of the TRAVERSE trial. Methods We utilized the TriNetX Research Network to identify a cohort of men ages 45-80 years old who met similar inclusion criteria to the TRAVERSE trial. We compared hypogonadal men (testosterone 100-300 ng/dL) who had a prescription for topical testosterone therapy and men who did not. Propensity score matching was used to match patient populations. Kaplan Meier survival analysis was used to determine the relative risk of new-onset AF and AKI within 3 years. Outcomes New-onset AF and AKI within 3 years. Results There were 2134 men included in each cohort after propensity score matching. Men on TRT had significantly lower testosterone (T) at the time of diagnosis compared to men not prescribed TRT (207 ± 66 ng/dL vs 246 ± 140 ng/dL, P  < 0.001). Kaplan–Meier survival analysis showed a significantly increased risk of AKI among men on TRT (RR 1.53, 95% CI 1.07-2.18). However, TRT was not associated with a significantly increased risk of new-onset AF (RR 1.48, 95% CI 0.93-2.37). Clinical Implications Hypogonadal men with underlying cardiovascular risk factors or pre-existing cardiovascular disease who receive TRT may be at increased risk of AKI after starting therapy. Strengths and Limitations We evaluated a large global research database and utilized similar inclusion and exclusion to the TRAVERSE trial. However, our results are limited by the retrospective study design and reliance on documented claims data. Conclusion Similar to the TRAVERSE trial, our study demonstrated an increased risk of AKI among men on TRT, but did not find increased risk of AF. However, further studies are required to validate these results. [ABSTRACT FROM AUTHOR]

Anabolic steroid therapy has been associated with tendon injury, but there is a paucity of evidence associating physiologic testosterone replacement therapy (TRT) with tenosynovitis of the hand, specifically trigger finger and de Quervain tenosynovitis. The purpose of this study was to evaluate the relationship between TRT and tenosynovitis of the hand. This was a one-to-one exact matched retrospective cohort study using a large nationwide claims database. Records were queried between 2010 and 2019 for adult patients who filled a prescription for TRT for 3 consecutive months. Rates of new onset trigger finger and de Quervain tenosynovitis and subsequent steroid injection or surgery were identified using ICD-9, ICD-10, and Current Procedural Terminology billing codes. Single-variable chi-square analyses and multivariable logistic regression were used to compare rates in the TRT and control cohorts while controlling for potential confounding variables. Both unadjusted and adjusted odds ratios (OR) are reported for each comparison. In the adjusted analysis, patients undergoing TRT were more than twice as likely to develop trigger finger compared to their matched controls. TRT was also associated with an increased likelihood of experiencing de Quervain tenosynovitis. Of the patients diagnosed with either trigger finger or de Quervain tenosynovitis over the 2-year period, patients with prior TRT were roughly twice as likely to undergo steroid injections or surgical release for both trigger finger and de Quervain tenosynovitis compared to the controls. TRT is associated with an increased likelihood of both trigger finger and de Quervain tenosynovitis, and an increased likelihood of requiring surgical release for both conditions. Prognostic II. [ABSTRACT FROM AUTHOR]

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Recent results from the Cardiovascular Trial of the Testosterone Trials showed that testosterone treatment of older men with low testosterone was associated with greater progression of noncalcified plaque (NCP). We evaluated the effect of anthropometric measures and cardiovascular biomarkers on plaque progression in individuals in the Testosterone Trial. The Cardiovascular part of the trial included 170 men aged 65 years or older with low testosterone. Participants received testosterone gel or placebo gel for 12 months. The primary outcome was change in NCP volume from baseline to 12 months, as determined by coronary computed tomography angiography (CCTA). We assayed several markers of cardiovascular risk and analyzed each marker individually in a model as predictive variables and change in NCP as the dependent variable. Of 170 enrollees, 138 (73 testosterone, 65 placebo) completed the study and were available for the primary analysis. Of 10 markers evaluated, none showed a significant association with the change in NCP volume, but a significant interaction between treatment assignment and waist-hip ratio (WHR) (P = 0.0014) indicated that this variable impacted the testosterone effect on NCP volume. The statistical model indicated that for every 0.1 change in the WHR, the testosterone-induced 12-month change in NCP volume increased by 26.96 mm3 (95% confidence interval, 7.72-46.20). Among older men with low testosterone treated for 1 year, greater WHR was associated with greater NCP progression, as measured by CCTA. Other biomarkers and anthropometric measures did not show statistically significant association with plaque progression.

Copyright of Magyar Nőorvosok Lapja is the property of Hungarian Society of Obsterics & Gynaecology and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Testosterone replacement therapy (TRT) can improve quality of life for men with hypogonadism. However, it is generally avoided in patients with a history of prostate cancer or breast cancer as there is uncertainty about risks. This case illustrates an example of synchronous metastatic prostate cancer and male breast cancer following TRT. A 72-year-old man with previously treated intermediate-risk prostate adenocarcinoma experienced a gradual rise in prostate-specific antigen (PSA) while self-administering testosterone replacement. He was later found to have recurrent metastatic prostate cancer and prior to initiating androgen deprivation therapy (ADT), he was also diagnosed with male breast cancer. His treatment has consisted of continued ADT for metastatic castration-sensitive prostate cancer (mCSPC) as well as surgical resection of his breast cancer. ADT plays a role in treatment of male breast cancer and prostate cancer. TRT remains relatively contraindicated in patients with a history of these malignancies, but the evidence supporting this recommendation is somewhat limited. This case highlights the potential risk for synchronous recurrent prostate and new male breast cancer following TRT. Further studies are needed to better elucidate the increased risks of these malignancies with TRT. • Testosterone replacement is avoided with a history of prostate or breast cancer. • This case shows prostate and male breast cancer following testosterone replacement. • Further studies need to clarify the risks of these malignancies with testosterone. [ABSTRACT FROM AUTHOR]

Hypogonadism is common in men with sickle cell disease (SCD) with prevalence rates as high as 25%. Testicular failure (primary hypogonadism) is established as the principal cause for this hormonal abnormality, although secondary hypogonadism and compensated hypogonadism have also been observed. The underlying mechanism for primary hypogonadism was elucidated in a mouse model of SCD, and involves increased NADPH oxidase-derived oxidative stress in the testis, which reduces protein expression of a steroidogenic acute regulatory protein and cholesterol transport to the mitochondria in Leydig cells. In all men including those with SCD, hypogonadism affects physical growth and development, cognition and mental health, sexual function, as well as fertility. However, it is not understood whether declines in physical, psychological, and social domains of health in SCD patients are related to low testosterone, or are consequences of other abnormalities of SCD. Priapism is one of only a few complications of SCD that has been studied in the context of hypogonadism. In this pathologic condition of prolonged penile erection in the absence of sexual excitement or stimulation, hypogonadism exacerbates already impaired endothelial nitric oxide synthase/cGMP/phosphodiesterase-5 molecular signaling in the penis. While exogenous testosterone alleviates priapism, it disadvantageously decreases intratesticular testosterone production. In contrast to treatment with exogenous testosterone, a novel approach is to target the mechanisms of testosterone deficiency in the SCD testis to drive endogenous testosterone production, which potentially decreases further oxidative stress and damage in the testis, and preserves sperm quality. Stimulation of translocator protein within the transduceosome of the testis of SCD mice reverses both hypogonadism and priapism, without affecting intratesticular testosterone production and consequently fertility. Ongoing research is needed to define and develop therapies that restore endogenous testosterone production in a physiologic, mechanism-specific fashion without affecting fertility in SCD men. [ABSTRACT FROM AUTHOR]

The concentration of androgens in men has a tendency to decrease with age. Androgen deficiency, also known as low testosterone in men, is associated with an increased risk of morbidity. The current solution for treating androgen deficiency is testosterone replacement therapy, but this intervention is not ideal either. Testosterone replacement can exacerbate preexisting conditions such as prostate disease. An alternative solution may be the use of dietary supplements to increase testosterone synthesis in men with androgen deficiency. On the other hand, an increase in testosterone above the optimal level can have major disadvantages, from prostate cancer to cardiovascular disease. and abnormal aggression. A randomized, placebo- controlled clinical trial showed that Ashwagandha increased testosterone levels in men with ages between 18 and 50 who took 300 mg of Ashwagandha root extract twice a day for 8 weeks. Testosterone levels increased by 534.38% compared to the placebo group; this significant increase may be too intense for men who want a minimal increase to correct tesosterone levels. The current experiment aims to demonstrate through a comparative analysis between the study and the experiment whether the Ashwagandha root powder will increase testosterone levels in two volunteers, aged 20 and 30 years old, and whether this increase will be more moderate than in the previous study. Demonstrating that Ashwagandha can also be used for moderate increases in testosterone levels over longer periods of time, the hypothesis is that Ashwagandha root powder will be a more ideal option than Ashwagandha root extract for men who want a small and constant increase of testosterone levels for long periods, because the powder has a lower potency than the extract, with a lower possibility of overdose, being more advantageous in older men. [ABSTRACT FROM AUTHOR]

Hypogonadism is common in men with sickle cell disease (SCD) with prevalence rates as high as 25%. Testicular failure (primary hypogonadism) is established as the principal cause for this hormonal abnormality, although secondary hypogonadism and compensated hypogonadism have also been observed. The underlying mechanism for primary hypogonadism was elucidated in a mouse model of SCD, and involves increased NADPH oxidase-derived oxidative stress in the testis, which reduces protein expression of a steroidogenic acute regulatory protein and cholesterol transport to the mitochondria in Leydig cells. In all men including those with SCD, hypogonadism affects physical growth and development, cognition and mental health, sexual function, as well as fertility. However, it is not understood whether declines in physical, psychological, and social domains of health in SCD patients are related to low testosterone, or are consequences of other abnormalities of SCD. Priapism is one of only a few complications of SCD that has been studied in the context of hypogonadism. In this pathologic condition of prolonged penile erection in the absence of sexual excitement or stimulation, hypogonadism exacerbates already impaired endothelial nitric oxide synthase/cGMP/phosphodiesterase-5 molecular signaling in the penis. While exogenous testosterone alleviates priapism, it disadvantageously decreases intratesticular testosterone production. In contrast to treatment with exogenous testosterone, a novel approach is to target the mechanisms of testosterone deficiency in the SCD testis to drive endogenous testosterone production, which potentially decreases further oxidative stress and damage in the testis, and preserves sperm quality. Stimulation of translocator protein within the transduceosome of the testis of SCD mice reverses both hypogonadism and priapism, without affecting intratesticular testosterone production and consequently fertility. Ongoing research is needed to define and develop therapies that restore endogenous testosterone production in a physiologic, mechanism-specific fashion without affecting fertility in SCD men.

Objective: The objective is to evaluate the efficacy and safety of testosterone supplementation in testicular cancer survivors with treatment-related hypogonadism., Data Sources: This systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards and used Embase, PubMed/MEDLINE, Cochrane Central, Web of Science Core Collection, Korean Journal Index, SciELO, and Global Index Medicus to obtain data in June of 2024., Study Selection and Data Extraction: Analyses evaluating testosterone supplementation in testicular cancer survivors with treatment-induced hypogonadism were included. Any analyses not assessing supplementation in this population or deemed unretrievable were excluded., Data Synthesis: Ten analyses were included for analysis. A total of 332 bilateral or unilateral testicular cancer survivors with treatment-influenced hypogonadism were reviewed, with 238 patients receiving testosterone replacement. Eight of the 10 analyses assessed participants without poor quality-of-life (QOL) metrics, metabolic factors, and bone mineral density (BMD) at baseline and only found a significant benefit in fat distribution metrics with testosterone supplementation. Two analyses evaluated participants with poor QOL metrics or BMD at baseline and showed improvements in QOL or BMD with testosterone supplementation., Relevance to Patient Care and Clinical Practice: There is robust evidence regarding the efficacy and safety of testosterone replacement in hypogonadal individuals but limited evidence specifically evaluating supplementation in testicular cancer survivors with treatment-influenced hypogonadism., Conclusions: The results suggest testosterone replacement may be beneficial in patients with impaired QOL metrics, metabolic factors, and BMD at baseline; the results also suggest that routine supplementation for all individuals in this patient population lacks efficacy., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Decreased testosterone levels are often under-recognized as a cause of anemia in males with hypogonadism. Men, as a subset, are less likely to seek medical care, especially those who struggle with complex psychiatric and social conditions, where they may lack full autonomy. Increasing testosterone levels leads to erythrocytosis by elevating erythropoietin and soluble transferrin receptor levels and suppressing hepcidin and ferritin levels. While practice guidelines on testosterone therapy for hypogonadism exist, there are no large-scale, randomized clinical trials assessing the use of testosterone replacement therapy in men with hypogonadism to evaluate its effect on anemia. Testosterone replacement therapy is also not wholly benign, and patients may be at increased risk for nonfatal cardiac arrhythmias, venous thromboembolism, and acute kidney injury. We explore two cases of patients with similar prior medical history, both of whom were found to have hypogonadism and anemia that were not otherwise explained. Both patients experienced significant improvement in their anemia following testosterone supplementation., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ali et al.)

Prader-Willi syndrome (PWS) is a rare genetic disorder typically characterized by body composition abnormalities, hyperphagia, behavioral challenges, cognitive dysfunction, and hormone deficiencies. Hypogonadism is common but knowledge on potential side effects of testosterone replacement is limited, in particular, the long-term effects on behavior and PSA. Retrospective case studies of seven men, median age 46 years, with genetically verified PWS, testosterone treated hypogonadism and available PSA values were included. Long-term follow-up of PSA was accessible in four patients. Medical records were reviewed for adverse effects. Five men were treated with intramuscular testosterone undecanoate, two had no hypogonadism. Median PSA was 0.68 μg/L (0.23–1.3), median testosterone 15 nmol/L. After a median time of 17 years of testosterone replacement median PSA was 0.75 μg/L (range 0.46–1.4). Testosterone replacement was well tolerated, and no major behavioral changes were reported. Five were treated with growth hormone for >20 years. Levels of PSA were low. Long-term treatment with testosterone was working well and did not result in any clinically meaningful increase in PSA. Our results indicate that testosterone replacement is neither associated with serious adverse events regarding changes in behavior or effect on PSA. However, larger studies are needed to confirm our results. • This case series of seven men with Prader-Willi syndrome showed: • Levels of prostate specific antigen (PSA) were low • Long-term testosterone treatment had no or limited effect on PSA • Long-term testosterone treatment was well tolerated • Awaiting more data, regular monitoring of PSA during testosterone treatment is recommended. [ABSTRACT FROM AUTHOR]

The substantial increase in life expectancy of men has focused growing attention on quality-of-life issues associated with reproductive aging. Serum total and free testosterone levels in men, after reaching a peak in the second and third decade of life, decline gradually with advancing age. The trajectory of age-related decline is affected by comorbid conditions, adiposity, medications, and genetic factors. Testosterone treatment of older men with low testosterone levels improves overall sexual activity, sexual desire, and erectile function; improves areal and volumetric bone density, as well as estimated bone strength in the spine and the hip; corrects unexplained anemia of aging; increases skeletal muscle mass, strength and power, self-reported mobility, and some measures of physical function; and modestly improves depressive symptoms. The long-term effects of testosterone on major cardiovascular events and prostate cancer risk remain unclear. The Endocrine Society recommends against testosterone therapy of all older men with low testosterone levels but suggests consideration of treatment on an individualized basis in men who have consistently low testosterone levels and symptoms or conditions suggestive of testosterone deficiency. [ABSTRACT FROM AUTHOR]

Abstract Background Testosterone signals through the androgen receptor (AR) and AR knockout mice develop obesity, suggesting a functional association between AR and leptin signaling. Furthermore, physiological blood concentrations of testosterone have been found to inhibit the development of arteriosclerosis, obesity and diabetes. However, these findings have not been verified by testosterone replacement in animal models and whether or not testosterone acts directly by activating AR to enhance leptin signaling, or indirectly by its conversion into estrogen remains unclear. Therefore, we investigated the effect of exogenously supplemented testosterone on glucose and lipid metabolism. Methods Four-week-old male leptin receptor-knockout db/db mice were used as controls for a model of obesity retaining low testosterone. Mice were divided into sham-operated, castrated, or castrated and testosterone-supplemented groups and fed a high-fat diet (HFD) for 2 weeks from 5 weeks of age. Testosterone concentrations, blood glucose, plasma insulin levels, and intraperitoneal glucose tolerance and insulin tolerance were measured. At 7 weeks, triglyceride and glycogen content were measured in the liver and muscle. Lipid accumulation in the liver and soleus muscle was determined by immunohistochemistry with Oil Red O. Statistical analyses were performed using the Student’s t-test or ANOVA where applicable. Results Lower testosterone levels in db/db mice compared with wild type (WT) db/+ mice were associated with glucose intolerance and fatty liver. Furthermore, castrated male db/db mice at 4 weeks of age progressively developed glucose intolerance accompanying a 15% increase in liver fat. Male mice fed a HFD had lower levels of testosterone compared with those fed a normal diet. We found that exogenous testosterone replacement injected subcutaneously into castrated male db/db mice alleviated the exacerbation of fatty liver and glucose intolerance, suggesting a leptin-independent mechanism. This mechanism is most likely mediated through gonadal axis suppression in this mouse model. Conclusions In summary, testosterone may use a novel pathway to complement leptin signaling to regulate glucose and lipid metabolism, and thus offers a new therapeutic target to treat metabolic disorders.

Testosterone deficiency is common in men with cardiovascular disease (CVD), and randomized placebo-controlled trials (RCTs) have reported beneficial effects of testosterone therapy on exercise-induced cardiac ischemia in chronic stable angina, functional exercise capacity, maximum oxygen consumption during exercise (VO2max) and muscle strength in chronic heart failure (CHF), shortening of the Q-T interval, and improvement of some cardiovascular risk factors. Testosterone deficiency is associated with an adverse CV risk profile and mortality. Clinical and scientific studies have provided mechanistic evidence to support and explain the findings of the RCTs. Testosterone is a rapid-onset arterial vasodilator within the coronary circulation and other vascular beds including the pulmonary vasculature and can reduce the overall peripheral systemic vascular resistance. Evidence has demonstrated that testosterone mediates this effect on vascular reactivity through calcium channel blockade (L-calcium channel) and stimulates potassium channel opening by direct nongenomic mechanisms. Testosterone also stimulates repolarization of cardiac myocytes by stimulating the ultra-rapid potassium channel-operated current. Testosterone improves cardiac output, functional exercise capacity, VO2maxand vagally mediated arterial baroreceptor cardiac reflex sensitivity in CHF, and other mechanisms. Independent of the benefit of testosterone on cardiac function, testosterone substitution may also increase skeletal muscle glucose metabolism and enhance muscular strength, both factors that could contribute to the improvement in functional exercise capacity may include improved glucose metabolism and muscle strength. Testosterone improves metabolic CV risk factors including body composition, insulin resistance, and hypercholesterolemia by improving both glucose utilization and lipid metabolism by a combination of genomic and nongenomic actions of glucose uptake and utilization expression of the insulin receptor, glucose transporters, and expression on regulatory enzymes of key metabolic pathways. The effect on high-density lipoprotein-cholesterol (HDL-C) differs between studies in that it has been found to fall, rise, or have no change in levels. Testosterone replacement can suppress the levels of circulating pro-inflammatory cytokines and stimulate the production of interleukin-10 (IL-10) which has anti-inflammatory and anti-atherogenic actions in men with CVD. No effect on C-reactive protein has been detected. No adverse effects on clotting factors have been detected. RCTs have not clearly demonstrated any significant evidence that testosterone improves or adversely affects the surrogate markers of atherosclerosis such as reduction in carotid intima thickness or coronary calcium deposition. Any effect of testosterone on prevention or amelioration of atherosclerosis is likely to occur over years as shown in statin therapy trials and not months as used in testosterone RCTs. The weight of evidence from long-term epidemiological studies supports a protective effect as evidenced by a reduction in major adverse CV events (MACEs) and mortality in studies which have treated men with testosterone deficiency. No RCT where testosterone has been replaced to the normal healthy range has reported a significant benefit or adverse effect on MACE nor has any recent meta-analysis.

Objectives: The beneficial effects of testosterone replacement therapy (TRT) in men with late-onset hypogonadism (LOH) on the body composition and metabolic outcomes are well-established. A potential explanation might lie in the hormones, secreted from skeletal muscles, named "myokines". The aim of this study was to evaluate the effects of TRT on the levels of serum irisin in subjects with LOH.Study Design: A total 40 men with metabolic syndrome (MS) and LOH (measured serum testosterone concentration < 12 nmol/l). TRT with Testosterone Undecanoate (Nebido™) was performed at baseline and at week 6. Irisin serum concentration was determined at baseline and at week 18 by means of ELISA.Results: Circulating irisin was positively associated with serum testosterone (r = 0.283, p < 0.05). TRT has led to a statistically significant rise in circulating serum irisin levels (7.12 ± 0.76 mcg/ml versus 7.76 ± 0.75 mcg/ml; paired-samples t-test p < 0.001). ROC-analyses determined irisin to be predictive of treatment response (AUC = 0.741, p = 0.014).Conclusions: Irisin is positively associated with serum testosterone in a population of men with MS and LOH. TRT in these subjects has led to a significant improvement in associated clinical symptoms as well as to a significant rise in serum irisin levels. [ABSTRACT FROM AUTHOR]

Previous studies by ourselves and others have demonstrated that both obesity and testosterone deprivation have been related to cognitive decline. We have also shown that a prebiotic and n-acetyl cysteine (NAC) improved cognitive dysfunction in obese rats and castrated-male rats. However, the effects of NAC, a prebiotic (inulin), and a combination of the two on cognition in castrated-obese rats has never been investigated. The hypothesis was that NAC and inulin attenuated cognitive decline in castrated-obese rats by improving gut dysbiosis, and decreasing oxidative stress, glial activation and apoptosis. Male Wistar rats (n = 36) were fed with either a normal diet (ND: n = 6) or a high-fat diet (HFD: n = 30) for twenty-eight weeks. The resultant obese rats had a bilateral orchiectomy (ORX) and were randomly divided into five subgroups (n = 6/ subgroup). Each subgroup was treated with one of five therapies: a vehicle; testosterone replacement (2 mg/kg/day); NAC (100 mg/kg); inulin (10%, w/w), or a combination of the NAC and inulin for four weeks. The results demonstrated that castrated-obese rats developed gut dysbiosis, metabolic disturbance, brain pathologies, and cognitive decline. All of the pathological conditions in the brain were ameliorated to an equal extent by testosterone replacement, NAC, and inulin supplementation. Interestingly, a combination of NAC and inulin had the greatest beneficial effect on cognitive function by synergistically reducing hippocampal inflammation and ameliorating glial dysmorphology. These findings suggest that a combination of NAC and inulin may confer the greatest benefits in improving cognitive function in castrated-obese male rats. [ABSTRACT FROM AUTHOR]

Background: It is important to assess the prevalence of hypogonadism and to identify the correlation between hypogonadism and cancer treatment with quality of life (QoL) in germ cell tumor (GCT) survivors.Methods: This is a single-center, non-randomized, prospective observational study in GCT survivors 18-50 years of age previously treated with surgery and chemotherapy (S+C) or surgery alone (S). Patients completed a validated QoL questionnaire at baseline, 3, and 6 months. Patients received supplemental testosterone as clinically indicated. Mean QoL scores were compared between two treatment groups (S+C vs. S) and within each group between survivors with hypogonadism (serum testosterone level < 300 ng/dL) versus without. A two-sided independent-groups t test was used to compare means.Results: We evaluated 199 GCT survivors. At baseline, the prevalence of biochemical hypogonadism was 48% overall, 51% in S+C group, and 45% in S group (p = .4). Overall, there was no statistically significant difference in QoL scores between S+C and C groups, except the S+C group exhibited greater modified Aging Male Symptoms (AMS) at baseline and 6 months. Patients with hypogonadism reported more fatigue, poor sleep quality, and worse general health at baseline. There were no statistical differences in mean QOL scores between patients with testosterone < 300 ng/dL who received testosterone supplementation and who did not.Conclusion: A significant proportion of GCT survivors have low testosterone levels after platinum-based chemotherapy and surgery as well as with just surgery alone. GCT survivors treated with platinum-based chemotherapy exhibited more symptoms related to male aging compared with survivors treated with surgery alone. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of testosterone (T) on the maintenance of corpus cavernosum (CC) structure and apoptosis. Methods: Animals were divided into three groups: sham operation group (n = 8) underwent sham operation; Orchiectomized (Orchiec)+ oily vehicle group (n = 8) underwent bilateral orchiectomy and received a single dose of oily vehicle by intramuscular injection (i.m.) 30 days after orchiectomy; and Orchiec + T group (n = 8) underwent bilateral orchiectomy and received a single dose of T undecanoate 100 mg/kg i.m. 30 days after the surgery. Animals were euthanized 60 days after the beginning of the experiment with an anesthetic overdose of ketamine and xylazine. Blood samples and penile tissue were collected on euthanasia. Azan's trichrome staining was used to evaluate smooth muscle, Weigert's Fucsin-Resorcin staining was used to evaluate elastic fibers and Picrosirius red staining was used to evaluate collagen. Apoptosis was evaluated using TUNEL technique. Results: T levels decreased in Orchiec + oily vehicle when compared to sham operation and Orchiec + T groups (p

Aim: To explore the metabolic phenotype of obesity-related secondary hypogonadism (SH) in men pre-replacement and post-replacement therapy with long-acting intramuscular (IM) testosterone undecanoate (TU).Methods: A prospective observational pilot study on metabolic effects of TU IM in male obesity-related SH (hypogonadal [HG] group, n = 13), including baseline comparisons with controls (eugonadal [EG] group, n = 15). Half the subjects (n = 7 in each group) had type 2 diabetes mellitus (T2D). Baseline metabolic assessment on Human Metabolism Research Unit: fasting blood samples; BodPod (body composition), and; whole-body indirect calorimetry. The HG group was treated with TU IM therapy for 6-29 months (mean 14.8-months [SD 8.7]), and assessment at the Human Metabolism Research Unit repeated. T-test comparisons were performed between baseline and follow-up data (HG group), and between baseline data (HG and EG groups). Data reported as mean (SD).Results: Overall, TU IM therapy resulted in a statistically significant improvement in HbA1C (9 mmol/mol, P = 0.03), with 52% improvement in HOMA%B. Improvement in glycaemic control was driven by the HG subgroup with T2D, with 18 mmol/mol [P = 0.02] improvement in HbA1C. Following TU IM therapy, there was a statistically significant reduction in fat mass (3.5 Kg, P = 0.03) and increase in lean body mass (2.9 kg, P = 0.03). Lipid profiles and energy expenditure were unchanged following TU IM therapy. Comparisons between baseline data for HG and EG groups were equivalent apart from differences in testosterone, SHBG and basal metabolic rate (BMR).Conclusion: In men with obesity-related SH (including a subgroup with T2D), TU IM therapy improved glycaemic control, beta cell function, and body composition. [ABSTRACT FROM AUTHOR]

In the desert gerbil Gerbillus tarabuli (Thomas, 1902), cortisol is the main glucocorticosteroid produced by the adrenal glands. Plasma cortisol concentrations show highest values when testosterone is reduced and lowest values during the breeding season which occurs from early winter to late spring. In order to specify the implication of testicular androgens in these corticosteroid seasonal variations we investigated the effects induced by gonadectomy performed during the breeding season on the pituitary adrenal axis. The animals collected in winter were assessed into three groups: sham-operated (Controls; n = 13), gonadectomised (GDX; n = 13) and testosterone replaced gonadectomised (GDX + T; n = 13). Physiological replacement of testosterone enanthate (75 µg/100 g b.w./twice daily) was applied during one week, while GDX group received the vehicle (40 µL sesame oil) alone. The right adrenal glands removed from euthanized animals were fixed for histomorphometry and androgen receptors (ARs) immunohistochemistry and the left ones were frozen with plasma samples until hormonal assays. Gonadectomy induces the enlargement of the adrenal cortex essentially due to that of zonae fasciculata ( ZF ) and reticularis ( ZR ) and perimedullary connective tissue which is abundant in the gerbil adrenals. The ARs immunostaining present at both cytoplasmic and nucleus level, is enhanced intensely in the ZR and moderately in the ZF and zona glomerulosa ( ZG ) cells. GDX group shows reduced plasma ACTH concentration (p = 0.0126) by 61% despite the increase in cortisol concentration occurring both in plasma (+216%; p = 0.0436) and adrenal tissue (+117%; p = 0.0348). Plasma aldosterone is also enhanced significantly (p = 0.0147) by 189% but androstenedione synthesis increased in adrenal tissue (p = 0.0459) by 65% instead a decrease at circulatory level (p = 0.0355) by 58% due to lack of testicular origin. So, testosterone deprivation activates corticosteroidogenesis also evidenced by the adrenal structure changes and the gonadectomy-induced increase in the plasma cholesterol. All of the gonadectomy-induced responses are reversible after physiological testosterone replacement. We conclude that the assessment of circulating adrenocorticotropic hormone (ACTH) concentrations together with cortisol levels essentially, reflecting the hypothalamic–pituitary adrenal (HPA) axis feedback loop control during the annual endogenous changes of testosterone secretion, represents a well-adapted response of this desert species living in an extreme environment. [ABSTRACT FROM AUTHOR]

Testosterone deficiency is common in men with cardiovascular disease (CVD), and randomized placebo-controlled trials (RCTs) have reported beneficial effects of testosterone therapy on exercise-induced cardiac ischemia in chronic stable angina, functional exercise capacity, maximum oxygen consumption during exercise (VO2max) and muscle strength in chronic heart failure (CHF), shortening of the Q-T interval, and improvement of some cardiovascular risk factors. Testosterone deficiency is associated with an adverse CV risk profile and mortality. Clinical and scientific studies have provided mechanistic evidence to support and explain the findings of the RCTs. Testosterone is a rapid-onset arterial vasodilator within the coronary circulation and other vascular beds including the pulmonary vasculature and can reduce the overall peripheral systemic vascular resistance. Evidence has demonstrated that testosterone mediates this effect on vascular reactivity through calcium channel blockade (L-calcium channel) and stimulates potassium channel opening by direct nongenomic mechanisms. Testosterone also stimulates repolarization of cardiac myocytes by stimulating the ultra-rapid potassium channel-operated current. Testosterone improves cardiac output, functional exercise capacity, VO2max and vagally mediated arterial baroreceptor cardiac reflex sensitivity in CHF, and other mechanisms. Independent of the benefit of testosterone on cardiac function, testosterone substitution may also increase skeletal muscle glucose metabolism and enhance muscular strength, both factors that could contribute to the improvement in functional exercise capacity may include improved glucose metabolism and muscle strength. Testosterone improves metabolic CV risk factors including body composition, insulin resistance, and hypercholesterolemia by improving both glucose utilization and lipid metabolism by a combination of genomic and nongenomic actions of glucose uptake and utilization expression of the insulin receptor, glucose transporters, and expression on regulatory enzymes of key metabolic pathways. The effect on high-density lipoprotein-cholesterol (HDL-C) differs between studies in that it has been found to fall, rise, or have no change in levels. Testosterone replacement can suppress the levels of circulating pro-inflammatory cytokines and stimulate the production of interleukin-10 (IL-10) which has anti-inflammatory and anti-atherogenic actions in men with CVD. No effect on C-reactive protein has been detected. No adverse effects on clotting factors have been detected. RCTs have not clearly demonstrated any significant evidence that testosterone improves or adversely affects the surrogate markers of atherosclerosis such as reduction in carotid intima thickness or coronary calcium deposition. Any effect of testosterone on prevention or amelioration of atherosclerosis is likely to occur over years as shown in statin therapy trials and not months as used in testosterone RCTs. The weight of evidence from long-term epidemiological studies supports a protective effect as evidenced by a reduction in major adverse CV events (MACEs) and mortality in studies which have treated men with testosterone deficiency. No RCT where testosterone has been replaced to the normal healthy range has reported a significant benefit or adverse effect on MACE nor has any recent meta-analysis. [ABSTRACT FROM AUTHOR]