Testosterone replacement therapy and vascular thromboembolic events: a systematic review and meta-analysis

To evaluate the relationship between testosterone replacement therapy(TRT)and arterial and/or venous thrombosis in patients with pre-treatment total testosterone(TT)<12 nmol I^(-1),we performed a meta-analysis following the Population Intervention Comparison Outcome model.Population:men with TT<12 nmol I^(-1) or clear mention of hypogonadism in the inclusion criteria of patients;intervention:TRT;comparison:placebo or no therapy;outcomes:arterial thrombotic events(stroke,myocardial infarction[MI],upper limbs,and lower limbs),VTE(deep vein thrombosis[DVT],portal vein thrombosis,splenic thrombosis,and pulmonary embolism),and mortality.A total of 2423 abstracts were assessed for eligibility.Twenty-four studies,including 14 randomized controlled trials(RCTs),were finally included,with a total of 4027 and 310288 hypotestosteronemic male patients,from RCTs and from observational studies,respectively.Based on RCT-derived data,TRT did not influence the risk of arterial thrombosis(odds ratio[OR]=1.27,95%confidence interval[CI]:0.47-3.43,P=0.64),stroke(OR=1.34,95%CI:0.09-18.97,P=0.83),MI(OR=0.51,95%CI:0.11-2.31,P=0.39),VTE(OR=1.42,95%CI:0.22-9.03,P=0.71),pulmonary embolism(OR=1.38,95%CI:0.27-7.04,P=0.70),and mortality(OR=0.70,95%CI:0.20-2.38,P=0.56).Meanwhile,when only observational studies are considered,a significant reduction in the risk of developing arterial thrombotic events,Ml,venous thromboembolism,and mortality was observed.The risk for DVT remains uncertain,due to the paucity of RCT-based data.TRT in men with TT<12 nmol I^(-1) is safe from the risk of adverse cardiovascular events.Further studies specifically assessing the risk of DVT in men on TRT are needed.

Testosterone replacement therapy improves insulin sensitivity and decreases high sensitivity C-reactive protein levels in hypogonadotropic hypogonadal young male patients

Background Many clinical studies suggest the inverse relationship between testosterone levels and insulin sensitivity in men, however the causative relationship of these two events is still not determined. The purpose of this study was to investigate the effects of testosterone replacement therapy （TRT） on insulin sensitivity, body composition, serum lipid profiles and high sensitivity C-reactive protein （hsCRP） in hypogonadotropic hypogonadal （HH） puberty undeveloped male patients. Methods In this prospectively designed study, we compared homeostasis model assessment of insulin resistance （HOMA-IR）, insulin areas under the curves （AUC） of 3-hour oral glucose tolerance test （OGTT） and other metabolic parameters between 26 HH patients and 26 healthy men. The patients＇ HOMA-IR, insulin AUC, body composition, lipid profiles, hsCRP and other parameters were compared before and after nine-month TRT. Results The average levels of total testosterone （TT） in HH and healthy group were （0.9±0.6） nmol/L and （18.8±3.4） nmol/L, respectively. HOMA-IR in HH group was significantly higher than the healthy group （5.14±5.16 vs 2.00±1.38, P 〈0.005）. Insulin AUC in 3-hour OGTT in HH group was significantly higher than the healthy group （698.6±414.7 vs 414.2±267.5, P 〈0.01）. Fasting glucose level in H H group was significantly higher than control group （（5.1±0.6） mmol/L vs （4.7±0.3） mmol/l, P 〈0.005）. Height, weight and grasp strength of the patients were significantly increased after 9-month TRT. Significant reductions in HOMA-IR （from 5.14±5.16 to 2.97±2.16, P 〈0.01）, insulin AUC （from 698.6±414.7 to 511.7±253.9, P 〈0.01） and hsCRP （from （1.49±1.18） mg/L to （0.70±0.56） mg/L, P 〈0.05） were found after TRT. Serum total cholesterol, LDL-C, HDL-C and triglyceride were all decreased, albeit with no significant difference compared to the level prior to TRT. Conclusions HOMA-IR, insulin AUC and fasting glucose level in HH young male patients were significantly higher than those of the control group, which suggests that low level of testosterone in male adolescents might be a risk factor for insulin resistance. TRT can significantly improve patients＇ insulin sensitivity and suppress serum hsCRP, which in return suggests that TRT may prevent the HH patients from developing diabetes mellitus and cardiovascular diseases （CVD） in future.

Recovery of spermatogenesis following testosterone replacement therapy or anabolic-androgenic steroid use

The use of testosterone replacement therapy （TRT） for hypogonadism continues to rise, particularly in younger men who may wish to remain fertile. Concurrently, awareness of a more pervasive use of anabolic-androgenic steroids （AAS） within the general population has been appreciated. Both TRT and AAS can suppress the hypothalamic-pituitary-gonadal （HPG） axis resulting in diminution of spermatogenesis. Therefore, it is important that clinicians recognize previous TRT or AAS use in patients presenting for infertility treatment. Cessation of TRT or AAS use may result in spontaneous recovery of normal spermatogenesis in a reasonable number of patients if allowed sufficient time for recovery. However, some patients may not recover normal spermatogenesis or tolerate waiting for spontaneous recovery. In such cases, clinicians must be aware of the pathophysiologic derangements of the HPG axis related to TRT or AAS use and the pharmacologic agents available to reverse them. The available agents include injectable gonadotropins, selective estrogen receptor modulators, and aromatase inhibitors, but their off-label use is poorly described in the literature, potentially creating a knowledge gap for the clinician. Reviewing their use clinically for the treatment of hypogonadotropic hypogonadism and other HPG axis abnormalities can familiarize the clinician with the manner in which they can be used to recover spermatogenesis after TRT or AAS use.

restosterone replacement therapy for late-onsel lypogonadism： current trends in Korea

Testosterone levels in men older than 40 years can decrease at a rate of 1%-2% per year, and reports show that more than 50% of 80-year-old men have testosterone levels consistent with hypogonadism. Late-onset hypogonadism （LOH） is a clinical and biochemical syndrome associated with advancing age and characterized by typical symptoms of serum testosterone deficiency. In recent decades, the concept of LOH in ageing men has become familiar in European countries and the United States. It is also a topic of interest and debate throughout Korea. However, most of the data regarding advantages or disadvantages of testosterone replacement therapy （TRT） as treatment for LOH have been primarily obtained from studies on Western populations; therefore, studies of the effects of TRT in Asian men, who may have different serum testosterone compared to Western men, are needed. TRT is commonly prescribed in Korea, despite the paucity of studies on the effects of TRT in Asian populations. Data from various TRT studies based on Korean have shown its efficacy in increasing serum testosterone levels and improving subjective symptoms as assessed by questionnaires. Currently, patches and short-acting intramuscular injections are displaced by gels and long-acting formulations. However, to prevent overdiagnosis and overtreatment, indication for TRT should include both low testosterone levels and symptoms and signs of hypogonadism.

Management of male obesity-related secondary hypogonadism:A clinical update

The global obesity pandemic has resulted in a rise in the prevalence of male obesity-related secondary hypogonadism(MOSH)with emerging evidence on the role of testosterone therapy.We aim to provide an updated and practical approach towards its management.We did a comprehensive literature search across MEDLINE(via PubMed),Scopus,and Google Scholar databases using the keywords“MOSH”OR“Obesity-related hypogonadism”OR“Testosterone replacement therapy”OR“Selective estrogen receptor modulator”OR“SERM”OR“Guidelines on male hypogonadism”as well as a manual search of references within the articles.A narrative review based on available evidence,recommendations and their practical implications was done.Although weight loss is the ideal therapeutic strategy for patients with MOSH,achievement of significant weight reduction is usually difficult with lifestyle changes alone in real-world practice.Therefore,androgen administration is often necessary in the management of hypogonadism in patients with MOSH which also improves many other comorbidities related to obesity.However,there is conflicting evidence for the appropriate use of testosterone replacement therapy(TRT),and it can also be associated with complications.This evidence-based review updates the available evidence including the very recently published results of the TRAVERSE trial and provides comprehensive clinical practice pearls for the management of patients with MOSH.Before starting testosterone replacement in functional hypogonadism of obesity,it would be desirable to initiate lifestyle modification to ensure weight reduction.TRT should be coupled with the management of other comorbidities related to obesity in MOSH patients.Balancing the risks and benefits of TRT should be considered in every patient before and during longterm management.

Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes

AIMTo determine how statins, testosterone (T) replacement therapy (TRT) and phosphodiesterase 5-inhibitors (PDE5I) influence age related mortality in diabetic men.METHODSWe studied 857 diabetic men screened for the BLAST study, stratifying them (mean follow-up = 3.8 years) into: (1) Normal T levels/untreated (total T > 12 nmol/L and free T > 0.25 nmol/L), Low T/untreated and Low T/treated; (2) PDE5I/untreated and PDE5I/treated; and (3) statin/untreated and statin/treated groups. The relationship between age and mortality, alone and with T/TRT, statin and PDE5I treatment was studied using logistic regression. Mortality probability and 95%CI were calculated from the above models for each individual.RESULTSAge was associated with mortality (logistic regression, OR = 1.10, 95%CI: 1.08-1.13, P < 0.001). With all factors included, age (OR = 1.08, 95%CI: 1.06-1.11, P < 0.001), Low T/treated (OR = 0.38, 95%CI: 0.15-0.92, P = 0.033), PDE5I/treated (OR = 0.17, 95%CI: 0.053-0.56, P = 0.004) and statin/treated (OR = 0.59, 95%CI: 0.36-0.97, P = 0.038) were associated with lower mortality. Age related mortality was as described by Gompertz, r2 = 0.881 when Ln (mortality) was plotted against age. The probability of mortality and 95%CI (from logistic regression) of individuals, treated/untreated with the drugs, alone and in combination was plotted against age. Overlap of 95%CI lines was evident with statins and TRT. No overlap was evident with PDE5I alone and with statins and TRT, this suggesting a change in the relationship between age and mortality.CONCLUSIONWe show that statins, PDE5I and TRT reduce mortality in diabetes. PDE5I, alone and with the other treatments significantly alter age related mortality in diabetic men.

Bulbocavernosus muscle area as a novel marker for hypogonadism

Objective:Late-onset hypogonadism,or androgen deficiency in the aging male,is a significant cause of morbidity in older men.Many men in the low normal or equivocal range for low testosterone level exhibit signs and symptoms of hypogonadism.Serum testosterone is an imperfect maker for hypogonadism as symptoms vary greatly within the low to low normal range in addition to variations among testosterone assays.Perineal ultrasound can be effectively used to examine the bulbocavernosus muscle(BCM),an androgenized tissue that may be impacted by androgen receptor activity.Methods:This study was a retrospective analysis of men who underwent perineal ultrasound for hypogonadism.The ultrasound data were used to calculate the area of the BCM and correlate it with indices of hypogonadismin symptomatic men including free and total testosterone and dual-energy X-ray absorptiometry(DEXA).Results:The results demonstrate that there is a significant correlation between total and free testosterone and BCM area in hypogonadal patients.Comparison between BCM area and total testosterone showed R^2=0.061 and p=0.0187 and comparison between BCM area and free testosterone showed R^2=0.0957 and p=0.0034.In addition,low BCM was also correlated with DEXA results showing osteoporosis and osteopenia(R^2=0.2239,p=0.0027).Conclusion:There has been recent controversy over the safety of testosterone replacement therapy.This might be particularly important in men with hypogonadal symptoms but a low normal testosterone level.Our study investigated the use of perineal ultrasound to measure BCM as a surrogate marker for poor androgenized men presenting with hypogonadism.

Testosterone and metabolic syndrome

Controversies surround the usefulness of identifying patients with the metabolic syndrome （MetS）. Many of the components are accepted risk factors for cardiovascular disease （CVD）. Although the MetS as defined includes many men with insulin resistance, insulin resistance is not universal. The low total testosterone （TT） and sex hormone binding globulin （SHBG） levels in these men are best explained by the hyperinsulinism and increased inflammatory cytokines that accompany obesity and increased waist circumference. It is informative that low SHBG levels predict future development of the MetS. Evidence is strong relating low TT levels to CVD in men with and without the MetS; however, the relationship may not be causal. The recommendations of the International Diabetes Federation for managing the MetS include cardiovascular risk assessment, lifestyle changes in diet, exercise, weight reduction and treatment of individual components of the MetS. Unfortunately, it is uncommon to see patients with the MetS lose and maintain a 10% weight loss. Recent reports showing testosterone treatment induced dramatic changes in weight, waist circumference, insulin sensitivity, hemoglobin Alc levels and improvements in each of the components of the MetS are intriguing. While some observational studies have reported that testosterone replacement therapy increases cardiovascular events, the Food and Drug Administration in the United States has reviewed these reports and found them to be seriously flawed. Large, randomized, placebo-controlled trials are needed to provide more definitive data regarding the efficacy and safety of this treatment in middle and older men with the MetS and low TT levels.

Testosterone attenuates pulmonary epithelial inflammation in male rats of COPD model through preventing NRF1-derived NF-κB signaling

Testosterone deficiency is common in male patients with chronic obstructive pulmonary disease (COPD) and may correlate with the deterioration of COPD. Clinical research suggests that testosterone replacement therapy may slow the COPD progression, but the specific biological pathway remains unclear. In this study, we explored the effect of testosterone on pulmonary inflammation in male COPD rats. The animals were co-treated with lipopolysaccharide (LPS) and cigarette to induce COPD. In COPD rats, nuclear respiratory factor 1 (NRF1) and NF-κB p65 were upregulated. In cigarette smoke extract (CSE)-, LPS-, or the combination of CSE and LPS-treated L132 cells, NRF1 and p65 were also upregulated. Silencing NRF1 resulted in the downregulation of p65. ChIP‒seq, ChIP‒qPCR, and luciferase results showed that NRF1 transcriptionally regulated p65. Both male and female COPD rats showed an upregulated NRF1 level and similar pulmonary morphology. But NRF1 was further upregulated in male castrated rats. Further supplementing testosterone in castrated male rats significantly reduced NRF1, pulmonary lesions, and inflammation. Supplementation of testosterone also reduced the phosphorylation of p65 and IKKβ induced by LPS or CSE in L132 cells. Our results suggest that testosterone plays a protective role in pulmonary epithelial inflammation of COPD through inhibition of NRF1-derived NF-κB signaling and the phosphorylation of p65.