Safety Of Testosterone Replacement Therapy Research Articles

Cardiovascular safety of testosterone replacement therapy (TRAVERSE trial)

Despite some confusing conclusions among recent findings from the TRAVERSE trial, the results should provide physicians with reassuring evidence to enable them to manage men with symptomatic testosterone deficiency with greater confidence.

Association between testosterone replacement therapy and cardiovascular outcomes: A meta-analysis of 30 randomized controlled trials.

The Cardiovascular safety of testosterone replacement therapy (TRT) among men with hypogonadism is not well established to date. Hence, we sought to evaluate the cardiovascular disease (CVD) outcomes among patients receiving testosterone therapy by using all recently published randomized controlled trials. We performed a systematic literature search on PubMed, EMBASE, and Clinicaltrial.gov for relevant randomized controlled trials (RCTs) from inception until September 30th, 2023. A total of 30 randomized trials with 11,502 patients were included in the final analysis. The mean age was ranging from 61.61 to 61.82years. Pooled analysis of primary and secondary outcomes showed that the incidence of any CVD events (OR, 1.12 (95%CI: 0.77-1.62), P=0.55), stroke (OR, 1.01 (95%CI: 0.68-1.51), P=0.94), myocardial infarction (OR, 1.05 (95%CI: 0.76-1.45), P=0.77), all-cause mortality (OR, 0.94 (95%CI: 0.76-1.17), P=0.57), and CVD mortality (OR, 0.87 (95%CI: 0.65-1.15), P=0.31) was comparable between TRT and placebo groups. Our analysis indicates that for patients with hypogonadism, testosterone replacement therapy does not increase the CVD risk and all-cause mortality.

Endocrinology: what's new in 2023

This overview provides a selection of studies published in 2023 with an impact on clinical practice. In reproductive endocrinology, important studies have addressed fertility preservation in men with Klinefelter's syndrome, the cardiovascular safety of testosterone replacement therapy, and a novel therapy, fezolinetant, for vasomotor symptoms of menopause. The updated European recommendations concerning adrenal incidentalomas will considerably modify current clinical practice. Based on a solid epidemiological work, the prevalence of pituitary adenomas has been confirmed to affect about 1 per 1000 individuals. Finally, a large British study allows to refine the benefit-risk profile of the three options available for the treatment of hyperthyroidism.

Testosterone replacement therapy is not associated with increased prostate cancer incidence, prostate cancer-specific, or cardiovascular disease-specific mortality in Finnish men

Background Concerns have been expressed over the safety of testosterone replacement therapy (TRT) in men with late-onset hypogonadism (LOH). Previous studies have shown controversial results regarding the association of TRT with the risk of cardiovascular events or prostate cancer (PCa) incidence, aggressiveness, and mortality. This study explores the overall risk of PCa and risk by tumor grade and stage, as well as mortality from PCa and cardiovascular disease (CVD), among men treated with TRT compared to men without LOH and TRT use. Materials and methods The study included 78,615 men of age 55–67 years at baseline from the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). Follow-up started at randomization and ended at death, emigration, or a common closing date January 1st, 2017. Cox proportional hazards regression model with time-dependent variables and adjustment for age, trial arm, use of other medications, and Charlson comorbidity index was used. Comprehensive information on TRT purchases during 1995–2015 was obtained from the Finnish National Prescription Database. PCa cases were identified from the Finnish Cancer Registry and causes of death obtained from Statistics Finland. Results Over the course of 18 years of follow-up, 2919 men were on TRT, and 285 PCa cases were diagnosed among them. TRT users did not exhibit a higher incidence or mortality rate of PCa compared to non-users. On the contrary, men using TRT had lower PCa mortality than non-users (HR = 0.52; 95% CI 0.3–0.91). Additionally, TRT users had slightly lower CVD and all-cause mortality compared to non-users (HR = 0.87; 95% CI 0.75–1.01 and HR = 0.93; 95% CI 0.87–1.0, respectively). No time- or dose-dependency of TRT use was evident in any of the analyses. Conclusion Men using TRT were not associated to increased risk for PCa and did not experience increased PCa- or CVD-specific mortality compared to non-users. Further studies considering blood testosterone levels are warranted.

A Systematic review of studies assessing efficacy and cardiovascular safety of testosterone replacement therapy in men with late-onset hypogonadism due to obesity ± type 2 diabetes mellitus

A Systematic review of studies assessing efficacy and cardiovascular safety of testosterone replacement therapy in men with late-onset hypogonadism due to obesity ± type 2 diabetes mellitus

Testosterone Replacement Therapy in Chronic Kidney Disease Patients

(Background) The aim of our study was to evaluate the efficacy and safety of testosterone replacement therapy (TRT) in men with chronic kidney disease and hypogonadism on conservative and hemodialysis treatment. (Methods) The studied population consisted of 38 men on hemodialysis (HD), 46 men with CKD stages II-IV (predialysis group, PreD) and 35 men without kidney disease who were similar in age to others (control group). Serum total testosterone level (TT) was measured, and free testosterone level (fT) was calculated. Hypogonadism criteria according to the EAU definition were fulfilled by 26 men on HD (68.4%) and by 24 men from the PreD group (52%). Testosterone replacement therapy (TRT) with testosterone enanthate in intramuscular injections every 3 weeks was applied in 15 men from HD and in 14 men from PreD. The safety of TRT was monitored by measuring PSA and overhydration. (Results) A significant rise of TT and fT was observed after 3 months of TRT, but no significant changes were observed after 6 and 12 months in the HD and PreD group. An intensity of clinical symptoms of hypogonadism measured by ADAM (androgen deficiency in the ageing male) questionnaire gradually decreased, and the intensity of erectile dysfunction measured by the IIEF-5 (international index of erectile functioning) questionnaire also decreased after 3, 6 and 12 months of TRT in the HD and PreD group. (Conclusions) The applied model of TRT is effective in the correction of clinical signs of hypogonadism without a significant risk of overhydration or PSA changes.

Utility of Directly Measured Free Testosterone in Predicting Benefit of Testosterone Therapy in Men with Hypogonadal Symptoms and Normal Total Testosterone

ABSTRACT Introduction Hypogonadal symptoms, including decreased libido, erectile dysfunction, and decreased energy/fatigue, often related to a low total testosterone (TT) level, are common among aging men, affecting at least 20% of men age ≥ 45.(1) Testosterone exists in two main forms: bound to proteins (primarily SHBG and albumin) and largely inactive, and as unbound free testosterone (FT). Current guidelines from multiple professional associations advise clinicians to use the presence of hypogonadal symptoms along with low serum TT to determine the need for Testosterone Replacement Therapy (TRT). The use of FT levels to guide treatment has not been established. Equilibrium dialysis is the gold standard for measuring FT, but rarely used clinically due to practical limitations.(2,3) Many guidelines also discourage the use of commercially-available directly measured FT by analog enzyme immunoassay (EIA) due to variability and accuracy concerns.(3) Thus, in guideline-based practice, symptomatically hypogonadal men with normal TT levels but low EIA FT are not offered TRT, despite some evidence that these men may benefit from treatment.(2) Objective To examine the benefits and safety of TRT in men with hypogonadal symptoms who demonstrate a normal TT level but low directly measured FT, as measured by a single national lab company (LabCorp) using EIA. Methods The study is an analysis of prospectively-collected data for 63 consecutive men seen in our clinical practice with hypogonadal symptoms, normal TT (>265 ng/dL) and low FT (normal range 7.2-24.0pg/mL). All men began a standardized regimen of T-cypionate IM injections at a dose of 200mg every 2 weeks.(4) Men with prior TRT were excluded. Baseline blood tests were performed for TT, FT, E2, LH, PRL, CBC, and PSA. Follow up blood tests included TT, FT, E2, CBC, and PSA. Clinical response to TRT was based on documentation of improvement in hypogonadal symptoms, including ED as measured using the IIEF-5 questionnaire, as well as subjective patient reports of changes in libido, energy, etc. Results A total of 63 men with a mean age of 64.0 yrs. (range 34-86 yrs.) were included. Prior to TRT, mean TT was 375.3ng/dL (IQR [312.0-419.5]) and mean FT was 4.7pg/mL (3.9-5.8). At 3-month follow up, mean TT was 690.8 (420.8-883.8) and FT was 11.71 (7.4-14.1). Mean IIEF-5 score prior to TRT was 12.2 (5.0-19.8) and after TRT was 13.3 (5.8-21.3). Within the cohort, 85.4% reported subjective improvement in overall energy and libido after 3 months of TRT, with 59.4% of patients reporting significant improvement and 26% reporting mild but noticeable improvement. The remaining 14.6% reported minimal or no improvement. Nearly half reported improvement in erection function, assessed by IIEF-5 questionnaire. One patient (1.6%) developed de novo erythrocytosis, and three (4.8%) developed pathologic rise in PSA. Conclusions Our findings suggest that many men with hypogonadal symptoms, normal TT, and low EIA FT respond well to TRT, and that such treatment is safe. Until the creation of specific guidelines regarding use of FT to guide TRT treatment decisions, it may be of clinical benefit to treat men based on appropriate symptoms and low directly measured FT levels. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Boston Scientific

D-Chiro-Inositol improves testosterone levels in older hypogonadal men with low-normal testosterone: a pilot study

BackgroundSeveral recent journal articles report that d-chiro-inositol (DCI), primarily known as insulin second messenger, influences steroidogenesis. In particular, new evidence is arising on DCI ability to regulate aromatase expression and testosterone biosynthesis. In this regard, DCI administration could represent a good therapeutic opportunity in case of reduced levels of testosterone.Older men generally have lower testosterone concentrations than younger men, and recent randomized controlled trials have examined whether testosterone treatment might improve health outcomes in this age group. There is limited information about the safety of testosterone replacement therapy in these men, hence DCI could represent an interesting alternative for future trials. Therefore, this study aims to evaluate the effect of DCI treatment on testosterone levels in older male patient.ResultsTen older men with basal low testosterone levels were enrolled in this study. Patients took 600 mg of DCI, two-times per day, for 30 days. We evaluated hormonal and glycaemic parameters, weight, waist circumference, and Body-Mass Index at baseline (T0) and after 30 days (T1). Finally, all patients also filled in the standardized International Index of Erectile Function questionnaire and performed the Handgrip test at T0 and T1. Men receiving DCI showed increased androgen and reduced oestrogen concentrations, and improved glycaemic profiles. DCI was also associated with reduced weight, Body-Mass Index, waist circumference, and improved grip strength and self-reported sexual function. All these effects led to the improvement of sexual function and physical strength.ConclusionsIn this pilot study, DCI treatment improved the levels of testosterone and androstenedione at the expense of oestrogens in elder men with low basal levels of these hormones without adverse effects.Trial registrationClinicaltrials.gov: D-chiroinositol Administration in Hypogonadal Males, NCT04708249

Correlation Between Testosterone Replacement Treatment and Lower Urinary Tract Symptoms

Lower urinary tract symptoms (LUTS) are a cluster of voiding symptoms, such as weak stream, hesitancy, intermittency, urinary frequency, urgency, and nocturia. LUTS are frequent in elderly men and it considered the ultimate clinical symptoms of benign prostatic hyperplasia. With aging, male hypogonadism is increased which is defined as decreased ability of the testes to produce sperm and sex steroids because of a pituitary/hypothalamic, or testicular deficiency. In academic andrology associations, the term “male hypogonadism” is commonly used to categorize testosterone deficiency. Testosterone deficiency syndrome (TDS) is defined as a decrease in serum testosterone accompanied by symptoms such as libido decrease, depressive disorder, erectile dysfunction, and fatigue. Although the mechanism about testosterone-replacement therapy (TRT) effects on men with hypogonadism is not yet identified, TRT has been shown to effectively relieve the symptoms of TDS as well as LUTS by several studies. Although the present review demonstrates the effectiveness and safety of TRT in men with TDS by prior studies, future large scale of clinical trials should be conducted to present more high-quality evidence to clinicians and patients.

Testosterone replacement therapy and the risk of venous thromboembolism: A systematic review and meta-analysis of randomized controlled trials

IntroductionThe cardiovascular safety of testosterone replacement therapy (TRT) is controversial. While several studies have investigated the association between TRT and the risk of arterial thrombosis, limited information is available regarding its risk of venous thromboembolism (VTE). We aimed to compare the risk of VTE in men randomized to TRT versus placebo or active-comparator in a systematic review. MethodsWe searched Medline, EMBASE, CINAHL, CENTRAL, and clinical trial registries to identify randomized controlled trials (RCTs) comparing TRT to placebo in men aged ≥18 years. We assessed study quality using the Cochrane Risk of Bias assessment tool and the overall quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Data were pooled across RCTs using random-effects models. ResultsA total of 13 RCTs (n = 5050) were included in our meta-analysis. In all, 2636 men were randomized to testosterone, and 2414 men to placebo. Sample sizes ranged from 101 to 790 men, and TRT duration from 3 to 36 months. Five studies had a high risk of bias, largely driven by unclear randomization and outcome assessment. When data were pooled across RCTs, testosterone therapy was not associated with VTE compared with placebo (RR: 1.03, 95% CI: 0.49–2.14; I2: 0%; low-quality evidence). Similar estimates were obtained for deep vein thrombosis and pulmonary embolism outcomes. ConclusionsOur systematic review suggests that TRT is not associated with an increased risk of VTE. However, estimates were accompanied by a wide 95% CIs, and a clinically important increased risk cannot be ruled out.

Testosterone Replacement Therapy in Men with Untreated or Treated Prostate Cancer: Do We Have Enough Evidences?

PurposeTo investigate the oncologic safety of testosterone replacement therapy (TRT) in men with untreated or treated prostate cancer.Materials and MethodsWe systematically searched PubMed, Embase, and Cochrane library database from January 1941 to March 2019.ResultsIn total, 36 articles met the eligibility criteria for this systematic review. They included a total of 2,459 TRT-treated patients, with a median of 20 patients per study (range: 1–1,142). Except for four studies, all were single-armed studies with poor quality scores (median MINOR, 9 of 24). Of the 36 studies, prostate cancer was managed through active surveillance (AS), in 5 studies; radical prostatectomy, in 11 studies; radiation therapy, in 5 studies; multiple intervention modalities, in 5 studies; and systemic therapy, in 9 studies. In comparison with TRT-treated and untreated patients, the pooled risk ratio (RR) was not significantly higher than one in comparisons of risk for disease progression (pooled RR, 0.83; 95% confidence interval, 0.57–1.21). The results of systematic review implied that TRT might be harmful in men with advanced disease (progression rate: 38.5%–100.0%), who undergo AS (15.4%–57.1%), and who successfully treated but having high-risk disease (0.0%–50.0%).ConclusionsCompared to TRT-untreated patients, TRT-treated patients may not have increased risks for disease progression in prostate cancer. However, the quality of currently available evidence is extremely poor. TRT may be harmful in men with advanced disease burden, in those with untreated prostate cancer undergoing AS, and in those with successfully treated prostate cancer but having high-risk disease.

European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males: Endorsing organization: European Society of Endocrinology.

Evidence regarding functional hypogonadism, previously referred to as 'late-onset' hypogonadism, has increased substantially during the last 10year. To update the European Academy of Andrology (EAA) guidelines on functional hypogonadism. Expert group of academicians appointed by the EAA generated a series of consensus recommendations according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) system. The diagnosis of functional hypogonadism should be based on both the presence of clinical symptoms supported by repeatedly low morning fasting serum total testosterone (T) measured with a well-validated assay, after exclusion of organic causes of hypogonadism. Lifestyle changes and weight reduction should be the first approach in all overweight and obese men. Whenever possible, withdrawal/modification of drugs potentially interfering with T production should be advised. Testosterone replacement therapy (TRT) is contraindicated in men with untreated prostate or breast cancer, as well as severe heart failure. Severe low urinary tract symptoms and haematocrit >48%-50% represent relative contraindications for TRT. Prostate-specific antigen and digital rectal examination of the prostate should be undertaken in men >40years of age before initiating TRT to exclude occult prostate cancer. Transdermal T should be preferred for initiation of TRT, whereas gonadotrophin therapy is only recommended when fertility is desired in men with secondary hypogonadism. TRT is able to improve sexual function in hypogonadal men. Other potential positive outcomes of TRT remain uncertain and controversial. TRT can reliably improve global sexual function in men with hypogonadism in the short term. Long-term clinical benefits, and safety of TRT in functional hypogonadism, remain to be fully documented. Clinicians should therefore explicitly discuss the uncertainties and benefits of TRT and engage them in shared management decision-making.

Late-onset hypogonadism: Prostate safety.

There have always been concerns regarding testosterone replacement therapy and prostate safety because of the central role of testosterone in prostate tissue. Even though there is a body of evidence supporting that the benefits of testosterone replacement therapy outbalance the risks of prostate disease, this matter is still debatable and represents a common concern among testosterone prescribers. The aim of this article was to review the influence of testosterone on prostate pathophysiology and discuss the potential impact of testosterone replacement therapy on the most common prostate pathologies, including benign prostatic hyperplasia and prostate cancer. We have performed an extensive PubMed review of the literature examining the effects of testosterone replacement therapy on the prostate and its most common affections, especially in terms of safety. Testosterone replacement therapy has been shown to improve components of metabolic syndrome and decrease prostate inflammation, which is related to the worsening of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia. Studies evaluating the link between testosterone replacement therapy and benign prostatic hyperplasia/LUTS have mostly demonstrated no change in symptom scores and even some benefits. There are a significant number of studies demonstrating the safety of testosterone replacement therapy in individuals with late-onset hypogonadism and a history of prostate cancer. The most recently published guidelines have already acknowledged this fact and do not recommend against T treatment in this population, particularly in non-high-risk disease. Testosterone replacement therapy could be considered for most men with late-onset hypogonadism regardless of their history of prostate disease. However, a discussion about the risks and benefits of testosterone replacement therapy is always advised, especially in men with prostate cancer. Appropriate monitoring is mandatory.

Testosterone replacement therapy in male urolithiasis patients with metabolic syndrome

Urolithiasis is one of the most wide-spread kidney lesions in males and females all over the world. It is particularly important for males with hypogonadism and metabolic syndrome.
 The goal of the study is to assess the effectiveness and safety of Testosterone replacement therapy in males with hypogonadism and metabolic syndrome. Patients and methods. 465 male urolithiasis patients were studied. Mean age was 46 (38-54 years). All patients involved in the study had excessive body mass and obesity of various extent. Mean body mass was 92 (85-97 kg) and body mass index 40.5. More than 50% of the patients had Ischaemic Heart Disease, Cholelithiasis and Goiter. Essential Hypertension was present in 76.3% of cases. In more than 50% of the cases there was a combination of two or three nosological forms present. Depending on the replacement therapy used all patients were distributed into two groups: the main (300 patients) and the control one (165 patients).
 Results of the study. Testosterone replacement therapy proved to contribute to normalization of mineral and lipid metabolism as well as improvement of kidney function and restoration of normal bone tissue density. Analysis of 5-year relapse frequency demonstrated it to be considerably lower in the main group (10%) than in the control one (30%) which is astatistically valid difference (p < 0.05).
 Conclusion. Testosterone replacement therapy is a highly effective and safe method for urolithiasis therapy in males with hypogonadism.

Chronic Testosterone Deprivation Sensitizes the Middle-Aged Rat Brain to Damaging Effects of Testosterone Replacement

Introduction: An increasing number of middle-aged men are being screened for low testosterone levels and the number of prescriptions for various forms of testosterone replacement therapy (TRT) has increased dramatically over the last 10 years. However, the safety of TRT has come into question with some studies suggesting increased morbidity and mortality. Objective: Because the benefits of estrogen replacement in postmenopausal women and ovariectomized rodents are lost if there is an extended delay between estrogen loss and replacement, we hypothesized that TRT may also be sensitive to delayed replacement. Methods: We compared the effects of testosterone replacement after short-term (2 weeks) and long-term testosterone deprivation (LTTD; 10 weeks) in middle-aged male rats on cerebral ischemia, oxidative stress, and cognitive function. We hypothesized that LTTD would increase oxidative stress levels and abrogate the beneficial effects of TRT. Results: Hypogonadism itself and TRT after short-term castration did not affect stroke outcome compared to intact rats. However, after long-term hypogonadism in middle-aged male Fischer 344 rats, TRT exacerbated the detrimental behavioral effects of experimental focal cerebral ischemia, whereas this detrimental effect was prevented by administration of the free-radical scavenger tempol, suggesting that TRT exacerbates oxidative stress. In contrast, TRT improved cognitive performance in non-stroked rats regardless of the length of hypogonadism. In the Morris water maze, peripheral oxidative stress was highly associated with decreased cognitive ability. Conclusions: Taken together, these data suggest that TRT after long-term hypogonadism can exacerbate functional recovery after focal cerebral ischemia, but in the absence of injury can enhance cognition. Both of these effects are modulated by oxidative stress levels.

Effectiveness of nephrolithiasis surgical treatment on the background of replacement testosterone therapy

The goal of the study is to assess the effectiveness and safety of testosterone replacement therapy in males with androgenic deficiency and nephrolithiasis who require surgical treatment.
 Patients and methods. All in all 565 patients were involved in the study. In 226 of them (40%) surgical treatment was used. In a majority of these cases (90%) contact uretherolithotripsy was used. In half of the patients uretheroscopy had revealed large and long-lasting concrements. In order to assess the effectiveness of nephrolithiasis surgical treatment on the background of testosterone replacement treatment the assessment of hormonal status during pre- and postoperative periods was accomplished, duration and intensity of pain during the early post-operative period was evaluated as well as narcotic analgetics application frequency and the duration of antibacterial therapy and the stay in the hospital.
 Results of the study. Replacement testosterone therapy during the early postoperative period in male patients with nephrolithiasis and androgen deficit has been demonstrated to reduce the leukocyteuria duration and the need for antibacterial therapy thus decreasing the stay at the hospital. Replacement testosterone therapy in male patients with nephrolithiasis and androgen deficit who had dealt with surgical treatment has been shown to decrease the pain duration and intensity thus decreasing the need for narcotic analgetics. The use of replacement testosterone therapy in the complex treatment of nephrolithiasis in patients after surgery contributes to faster liquidation of hyperglycemia and normalization of carbohydrate metabolism. Replacement testosterone therapy in male patients with androgen deficit and nephrolithiasis who need surgical treatment contributes to reduction of kidney stone disease relapse rate.
 Conclusion. Replacement testosterone therapy in male patients with nephrolithiasis and androgen deficit who need surgical treatment considerably improve the postoperative period quality.

SAT-001 Supra-Physiological Testosterone Treatment Reduces Aortic Atheroma but Increases Markers of Cardiac Hypertrophy

Supra-physiological Testosterone Treatment Reduces Aortic Atheroma but Increases Markers of Cardiac Hypertrophy The impact of testosterone on the cardiovascular system is controversial and concerns have been raised in regard to the safety of testosterone replacement therapy (TTh) in hypogonadal men with cardiovascular disease. We have examined the effects of supra-physiological concentrations of testosterone upon aortic fatty streak formation in high-fat diet-fed testicular feminized (Tfm) mice, which exhibit non-functional androgen receptors (AR) and low circulating testosterone levels. Tfm mice were fed a high-cholesterol diet ad libitum for 28 weeks and received fortnightly intramuscular injections of either saline (Tfm, n=8, XY, n=8), 10uL of 250mg/mL testosterone alone (Tfm, n=8, XY, n=8), or in conjunction with either a 30uL intramuscular injection of 50mg/ml estrogen receptor-alpha antagonist fulvestrant (Tfm, n=8), or with 10mg/kg/day of aromatase inhibitor anastrazole in drinking water (Tfm, n=7). Cardiac tissue mRNA was analysed by qPCR for markers of hypertrophy (ANP, BNP, alpha-actin, MYH7, Gsk3-beta, SM22-alpha). A significant reduction in aortic fatty streak formation was observed in Tfm mice receiving supra-physiological testosterone compared to those receiving saline; 1.25+0.36% versus 2.85+0.37% respectively (p<0.01). No significant increase in aortic lipid deposition was observed in XY littermates administered supra-physiological testosterone compared to those receiving saline; 0.22+0.13% versus 0.32+0.12% respectively (p=ns). Aortic fatty streak formation in Tfm mice receiving supra-physiological testosterone in conjunction with fulvestrant or anastrazole was similar to that observed in Tfm mice receiving supra-physiological testosterone therapy alone; 0.71+0.18% and 1.09+0.81% respectively versus 1.25+0.36% (both p=ns) indicating non-genomic actions of testosterone. Hypertrophic markers and heart weights were elevated in XY littermates receiving supra-physiological testosterone but not in Tfm mice compared to placebo suggesting AR-dependent actions. This evidence suggests that supra-physiological levels of testosterone protect against diet induced aortic atheroma formation, at least in part, via non-genomic mechanisms but incur increased cardiovascular risk by potentially inducing cardiac hypertrophy via AR-dependent actions. Dose titration to physiological levels and careful monitoring of patients throughout treatment is key to eliciting the beneficial cardiovascular effects of TTh in hypogonadal men.

Cardiovascular and Cerebrovascular Safety of Testosterone Replacement Therapy Among Aging Men with Low Testosterone Levels: A Cohort Study

PurposeWe assessed the risk of ischemic stroke, transient ischemic attack, and myocardial infarction associated with testosterone replacement therapy (TRT) among aging men with low testosterone levels. MethodsUsing the UK Clinical Practice Research Datalink, we formed a cohort of men aged 45 years or older with low testosterone levels and no evidence of hypogonadotropic or testicular disease, between 1995 and 2017. Hazard ratios (HRs) and 95% confidence intervals (CIs) of a composite of ischemic stroke/transient ischemic attack and myocardial infarction were estimated using time-dependent Cox proportional hazards models, comparing current use of TRT with nonuse. ResultsThe cohort included 15,401 men. During 71,541 person-years of follow-up, 850 patients experienced an ischemic stroke/transient ischemic attack/myocardial infarction (crude incidence rate 1.19 [95% confidence interval (CI), 1.11-1.27] per 100 persons per year). Compared with nonuse, current use of TRT was associated with an increased risk of the composite outcome (HR 1.21; 95% CI, 1.00-1.46). This risk was highest in the first 6 months to 2 years of continuous TRT use (HR 1.35; 95% CI, 1.01-1.79), as well as among men aged 45-59 years (HR 1.44; 95% CI, 1.07-1.92). ConclusionsTRT may increase the risk of cardiovascular events in aging men with low testosterone levels, particularly in the first 2 years of use. In the absence of identifiable causes of hypogonadism, TRT should be initiated with caution among aging men with low testosterone levels.

MP58-12 SAFETY OF TESTOSTERONE REPLACEMENT AFTER RADIATION THERAPY FOR LOCALIZED PROSTATE CANCER: A POPULATION-BASED ANALYSIS

INTRODUCTION AND OBJECTIVES:The safety of testosterone replacement therapy in men who have undergone radiation therapy (RT) for localized prostate cancer remains undefined.METHODS:In a large nation...

PD28-12 SAFETY OF TESTOSTERONE REPLACEMENT THERAPY AFTER RADICAL PROSTATECTOMY (RP) FOR LOCALIZED PROSTATE CANCER: A POPULATION-BASED ANALYSIS

INTRODUCTION AND OBJECTIVES:The safety of testosterone replacement therapy in men who have undergone radical prostatectomy (RP) for localized prostate cancer remains undefined.METHODS:In a large na...