Plin4 exacerbates cadmium-decreased testosterone level via inducing ferroptosis in testicular Leydig cells.

Strong evidence indicates that environmental stressors are the risk factors for male testosterone deficiency (TD). However, the mechanisms of environmental stress-induced TD remain unclear. Based on our all-cause male reproductive cohort, we found that serum ferrous iron (Fe2⁺) levels were elevated in TD donors. Then, we explored the role and mechanism of ferroptosis in environmental stress-reduced testosterone levels through in vivo and in vitro models. Data demonstrated that ferroptosis and lipid droplet deposition were observed in environmental stress-exposed testicular Leydig cells. Pretreatment with ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, markedly mitigated environmental stress-reduced testosterone levels. Through screening of core genes involved in lipid droplets formation, it was found that environmental stress significantly increased the levels of perilipins 4 (PLIN4) protein and mRNA in testicular Leydig cells. Further experiments showed that Plin4 siRNA reversed environmental stress-induced lipid droplet deposition and ferroptosis in Leydig cells. Additionally, environmental stress increased the levels of METTL3, METTL14, and total RNA m6A in testicular Leydig cells. Mechanistically, S-adenosylhomocysteine, an inhibitor of METTL3 and METTL14 heterodimer activity, restored the abnormal levels of Plin4, Fe2⁺ and testosterone in environmental stress-treated Leydig cells. Collectively, these results suggest that Plin4 exacerbates environmental stress-decreased testosterone level via inducing ferroptosis in testicular Leydig cells.

Testomalacia.

In this communication, we introduce the descriptive diagnostic term 'testomalacia'. Testomalacia may suggest softness of the testes, both anatomic and/or functional, or may suggest malaise or illness related to testosterone secretion/function. While the term is not in vogue as of now, we feel that it describes functional androgen deficiency in an apt manner. Unlike other terms used to describe these symptoms, testomalacia can be used at any age, encompasses several etiologies and is just a single term rather than multiple complicated abbreviations.

Positive association between serum bilirubin within the physiological range and serum testosterone levels.

BACKGROUNDS: Research has demonstrated that elevated serum total bilirubin (STB) levels have a beneficial impact on various diseases, particularly metabolic syndrome. This study aims to investigate the association between STB levels and serum testosterone (STT) in order to determine if bilirubin plays a protective role in relation to testosterone deficiency (TD) risk. METHODS: In this study, a total of 6,526 eligible male participants aged 20 years or older were analyzed, all of whom took part in the National Health and Nutrition Examination Survey (NHANES) conducted between 2011 and 2016. To investigate the relationship between STB and STT levels, we employed weighted multivariate regression models along with restricted cubic splines (RCS). Additionally, a subgroup analysis was conducted to explore the heterogeneity of this relationship across different subpopulations. RESULTS: Among the participants, 1,832 individuals (28.07%) were identified as having testosterone deficiency (TD), defined as an STT level below 300 ng/dL. A significant positive correlation between STB and STT levels was observed in both crude and adjusted models (all P < 0.0001). The association between STB and STT levels was found to be statistically significant up to a threshold of 17.1 µmol/L, after which it became statistically insignificant(P for non-linearity = 0.0035). Weighted logistic regression analysis indicated that a 1 µmol/L increase in STB was associated with a 4% decrease in the likelihood of TD (odds ratio = 0.96, P < 0.0001). Subgroup analysis showed that the inverse relationship was limited to individuals aged 60 and over, non-smokers/drinkers, and obese individuals. CONCLUSION: STB within the physiological range(17.1 µmol/L) was positively associated with STT in adult males. The potential protective role of bilirubin regarding testosterone levels merits further exploration.

Association between varicocele and hypogonadism, or erectile dysfunction: A systematic review and meta-analysis.

OBJECTIVE: To assess the association between varicocele and hypogonadism, or erectile dysfunction. METHODS: We searched MEDLINE, EMBASE, LILACS, CENTRAL, and other sources. We included cohort, case-control, and cross-sectional studies. The primary outcome was the association between varicocele and hypogonadism, or erectile dysfunction, and the secondary outcome included semen analysis. We assessed the risk of bias with the Newcastle-Ottawa Scale. We performed statistical analysis in Review Manager 5.3 and reported information about the Odds Ratio (OR) with a 95% confidence interval. We produced a forest plot for the primary outcome. RESULTS: We included ten studies in qualitative analysis and six studies in quantitative analysis. Most of the cross-sectional studies showed a low risk of bias, not so for the two case-control studies, which represented a high risk of bias. Most of the reports described a correlation between having varicocele and presenting low testosterone levels: the meta-analysis showed that there is a significant association between varicocele and hypogonadism (OR 3.27 95% CI 1.23 to 8.68). Regarding varicocele and erectile, only one study showed a significant difference in erectile function in comparison to varicocele patients and men without varicocele. CONCLUSION: There is an association between varicocele presence and hypogonadism, although more studies are needed. Besides, not much is reported about an association between varicocele and erectile dysfunction, but impairment can occur through hormone disturbances.

Sexual health and testosterone concentration in male lymphoma survivors: A systematic review.

Advancements in lymphoma treatment have increased the number of long-term survivors who may experience late effects such as impaired sexual function and testosterone deficiency. The aim of this review was to determine the prevalence of testosterone deficiency and sexual dysfunction among male lymphoma survivors; and associations between the two. A systematic search identified 20 articles for inclusion. The prevalence of low total testosterone was 0%-50 %, with mean values within reference levels, and for luteinizing hormone above reference levels in 0%-80 %. Four studies included SHBG and free testosterone, with mixed results. Compromised sexual health was found in 23%-61 %. Overall, total testosterone and sexual health were associated. The risk of bias (ROBINS-E and RoB 2) was high/very high, leading to low/very low overall confidence in the bulk of evidence (GRADE). Longitudinal studies evaluating biologically active testosterone and sexual health are needed, to develop evidence based standard procedures for follow-up of sexual health.

Association between life's essential 8 and testosterone deficiency in US men: findings from national health and nutrition examination survey (NHANES) 2011-2016.

Background: Testosterone deficiency (TD) is closely associated with cardiovascular diseases (CVD). We intended to explore the association of Life's Essential 8 (LE8), the recently updated measurement of cardiovascular health, with the prevalence of TD among US male adults. Methods: The population-based cross-sectional study selected male adults aged 20 years or older from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2016. According to the American Heart Association definitions, the LE8 score was measured on a scale of 0-100, and divided into health behavior and health factor scores, simultaneously. Furthermore, these scores were categorized into low (0-49), moderate (50-79), and high (80-100) classifications. TD is defined as a total testosterone level below 300ng/dL. Correlations were investigated by weighted multivariable logistic regression, and the robustness of the results were verified by subgroup analysis. Results: A total of 4971 male adults with an average age of 47.46 ± 0.41 years were eligible for the final analyses, of whom 1372 were determined to have TD. The weighted mean LE8 score of the study population was 68.11 ± 0.41. After fully adjusting potential confounders, higher LE8 scores were significantly associated with low risk of TD (odd ratio [OR] for each 10-point increase, 0.79; 95% CI, 0.71-0.88) in a linear dose-response relationship. Similar patterns were also identified in the association of health factor scores with TD (OR for each 10-point increase, 0.74; 95% CI, 0.66-0.83). These results persisted when LE8 and health factor scores was categorized into low, moderate, and high groups. The inversed association of LE8 classifications and TD remained statistically significant among older, obese, and men without CVD. Conclusions: LE8 and its health factor subscales scores were negatively associated with the presence of TD in linear fashions. Promoting adherence to optimal cardiovascular health levels may be advantageous to alleviate the burden of TD.

Association between weight-adjusted waist index and testosterone deficiency in adult American men: findings from the national health and nutrition examination survey 2013-2016.

BACKGROUND: Testosterone deficiency (TD) and obesity are globally recognized health concerns, with a bidirectional causal relationship between them. And a newly discovered obesity indicator, the Weight-Adjusted-Waist Index (WWI), has been proposed, demonstrating superior adiposity identification capability compared to traditional body mass index (BMI) and waist circumference (WC) indicators. Therefore, we present the inaugural investigation into the associations of WWI with total testosterone levels and the risk of TD. METHODS: Data restricted to the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2016 were analyzed. Only males aged > 20 years who completed body measures and underwent serum sex hormone testing were potentially eligible for analysis. Weighted multivariable linear regression and logistic regression analyses were employed to investigate the relationships between WWI and total testosterone levels, and the risk of TD, respectively. Smooth curve fittings and weighted generalized additive model (GAM) regression were conducted to examine the linear relationship among them. Additionally, subgroup analyses with interaction tests were performed to assess the stability of the results. RESULTS: Finally, a total of 4099 participants with complete data on testosterone and WWI were included in the formal analysis. The mean age of study participants was 46.74 ± 0.35 years with a TD prevalence of 25.54%. After adjusting all potential confounders, the continuous WWI displayed a negative linear relationship with total testosterone levels (ß=-61.41, 95%CI: -72.53, -50.29, P < 0.0001) and a positive linear relationship with risk of TD (OR = 1.88, 95%CI: 1.47, 2.39, P < 0.0001). When WWI was transformed into quartiles as a categorical variable, participants in Q4 exhibited lower total testosterone levels (ß=-115.4, 95%CI: -142.34, -88.45, P < 0.0001) and a higher risk of TD (OR = 3.38, 95% CI: 2.10, 5.44, P < 0.001). These associations remained stable in subgroup analyses without significant interaction (all P for interaction > 0.05). CONCLUSIONS: This investigation firstly unveiled a negative linear association between WWI and total testosterone levels, coupled with a positive linear relationship with the prevalence of TD in U.S. male adults aged 20 years and older. Further studies are needed to validate the potential utility of WWI for the early identification and timely intervention of TD.

Association between life's essential 8 and testosterone deficiency in men: NHANES 2011-2016.

Background: Serum testosterone is intrinsically associated to cardiovascular disease. Our aim is to explore the relationship between the recently updated cardiovascular health measurement, known as Life's Essential 8 (LE8), and the prevalence of testosterone deficiency (TD) in adult males in the United States. Methods: Study data was obtained from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2016. A weighted multivariate logistic regression model was applied to evaluate the correlation between LE8 and testosterone deficiency. Restricted Cubic Spline (RCS) was employed to explore its non-linear relationship. In addition, a stratified analysis was conducted. Results: The final analysis included 2332 participants from NHANES from 2011 to 2016. After adjusting for confounding factors, the odds ratios (ORs) and 95% confidence intervals (CIs) for testosterone deficiency in participants with moderate and higher LE8 scores compared to the lowest LE8 scores were 0.59 (0.38-0.92) and 0.38 (0.19-0.76), respectively. The results of subgroup analysis showed that LE8 score was significantly associated with TD among young and middle-aged participants. Conclusion: A lower LE8 score is related to a higher incidence of testosterone deficiency, especially in young and middle-aged men. Further research is necessary to explore the potential mechanisms between them.

Testosterone deficiency worsens mitochondrial dysfunction in APP/PS1 mice.

Background: Recent studies show testosterone (T) deficiency worsens cognitive impairment in Alzheimer's disease (AD) patients. Mitochondrial dysfunction, as an early event of AD, is becoming critical hallmark of AD pathogenesis. However, currently, whether T deficiency exacerbates mitochondrial dysfunction of men with AD remains unclear. Objective: The purpose of this study is to explore the effects of T deficiency on mitochondrial dysfunction of male AD mouse models and its potential mechanisms. Methods: Alzheimer's disease animal model with T deficiency was performed by castration to 3-month-old male APP/PS1 mice. Hippocampal mitochondrial function of mice was analyzed by spectrophotometry and flow cytometry. The gene expression levels related to mitochondrial biogenesis and mitochondrial dynamics were determined through quantitative real-time PCR (qPCR) and western blot analysis. SH-SY5Y cells treated with flutamide, T and/or H2O2 were processed for analyzing the potential mechanisms of T on mitochondrial dysfunction. Results: Testosterone deficiency significantly aggravated the cognitive deficits and hippocampal pathologic damage of male APP/PS1 mice. These effects were consistent with exacerbated mitochondrial dysfunction by gonadectomy to male APP/PS1 mice, reflected by further increase in oxidative damage and decrease in mitochondrial membrane potential, complex IV activity and ATP levels. More importantly, T deficiency induced the exacerbation of compromised mitochondrial homeostasis in male APP/PS1 mice by exerting detrimental effects on mitochondrial biogenesis and mitochondrial dynamics at mRNA and protein level, leading to more defective mitochondria accumulated in the hippocampus. In vitro studies using SH-SY5Y cells validated T's protective effects on the H2O2-induced mitochondrial dysfunction, mitochondrial biogenesis impairment, and mitochondrial dynamics imbalance. Administering androgen receptor (AR) antagonist flutamide weakened the beneficial effects of T pretreatment on H2O2-treated SH-SY5Y cells, demonstrating a critical role of classical AR pathway in maintaining mitochondrial function. Conclusion: Testosterone deficiency exacerbates hippocampal mitochondrial dysfunction of male APP/PS1 mice by accumulating more defective mitochondria. Thus, appropriate T levels in the early stage of AD might be beneficial in delaying AD pathology by improving mitochondrial biogenesis and mitochondrial dynamics.

Assessing men with opioid use disorder for testosterone deficiency after the development of symptoms.

OBJECTIVE: Individuals with opioid use disorder (OUD) have reduced life expectancy and inferior outcomes when treated for depression, diabetes, and fractures. Their elevated risk of testosterone deficiency may contribute to all of these relationships, however few individuals prescribed opioids are evaluated with testosterone assays. The purpose of this study is to determine whether patients with opioid use disorder are evaluated for testosterone deficiency after development of a symptom that may merit investigation, such as erectile dysfunction (ED). METHOD: We conducted a retrospective longitudinal cohort study that utilized data from a national database called TriNetX. Patients were eligible for inclusion if they were 20 to 90 years of age, male, and diagnosed with erectile dysfunction. We utilized descriptive statistics and logistic regression to address study aims. RESULTS: Testosterone testing was uncommon for all patients with ED. Among 20,658 patients, it was assessed in 11.2% with OUD and 15.1% without OUD. Among those screened, 40% individuals with OUD and ED had testosterone deficiency. Odds of screening those with OUD were lower than matched controls (RR 0.74). CONCLUSIONS: Individuals with OUD are at increased risk of testosterone deficiency than the general population, but nearly 90% are not evaluated for this condition even after development symptoms. That 40% of individuals assessed were classified as testosterone deficient suggests endocrine disorders may be contributing to increased fracture risk, chronic pain, and severe depression commonly encountered in patients with OUD. Addressing this care gap may reduce morbidity and mortality associated with opioid use disorder.

Anemia and testosterone deficiency risk: insights from NHANES data analysis and a Mendelian randomization analysis.

BACKGROUND: Previous research has shown that testosterone deficiency (TD) increases the risk of anemia, but it is unclear whether anemia affects testosterone levels. This study investigated the influence of anemia on testosterone levels. METHODS: Utilizing data from six NHANES cycles, including demographic, testosterone levels, and hemoglobin concentrations, we employed multivariable-adjusted logistic regression to investigate the relationship between anemia and testosterone levels. Moreover, a two-sample Mendelian randomization (MR) study employing genome-wide association study (GWAS) data examined the causal relationship. Kaplan-Meier survival estimation was used to compared the overall survival (OS) of anemic and nonanemic patients with low testosterone and normal testosterone levels. RESULTS: The inclusion of 21,786 participants (2318 with anemia and19,468 without anemia) revealed that nonanemic patients exhibited higher testosterone levels than did anemic patients (ß = 22.616, 95% CI: 3.873-41.359, p = 0.01807). MR analysis confirmed anemia as a cause of TD (OR = 1.045, 95% CI: 1.020-1.071, p < 0.001). Anemic males with low testosterone had reduced OS compared to those with normal levels (p < 0.001). CONCLUSIONS: Anemia emerged as a potential risk factor for TD, highlighting a bidirectional relationship between these conditions. Additional prospective investigations are essential for the validation and reinforcement of our findings.

Analysis of diurnal variation in serum testosterone levels in men with symptoms of testosterone deficiency.

BACKGROUND: Testosterone (T) plays a crucial role in various physiological functions in men, and understanding the variations in T levels during the day is essential for diagnosing and treating testosterone deficiency (TD). AIM: We sought to evaluate the reduction in serum total T (TT) levels throughout the day in men with symptoms of testosterone deficiency and to determine the variables having an impact on the extent of this decline. METHODS: The study population consisted of a group of men who within 3 months of each other had all undergone both early morning and afternoon TT level measurements. We did not include patients with a history of a prior orchiectomy, testosterone levels below 100 ng/dL or above 1000 ng/dL, a history of androgen deprivation therapy, or patients on T therapy. Statistical analyses were conducted using descriptive statistics, t-tests, chi-square tests, and correlation calculations. Liquid chromatography-tandem mass spectrometry was used to measure TT, and a change in TT levels greater than 100 ng/dL was considered significant. Using multivariable and univariable analysis, we attempted to define predictors of a decrease in afternoon TT levels. OUTCOMES: The majority of men showed no significant difference in T levels between morning and afternoon. RESULTS: In total, 506 men with a median age of 65 years were analyzed. The most common comorbidities were hypertension and hyperlipidemia. Levels of TT were measured in the morning and afternoon, and no significant differences in mean T levels based on the time of the test were found. Age was not significantly associated with T levels. CLINICAL IMPLICATIONS: There was a weak negative correlation between age and the difference between morning and afternoon T levels, with younger men showing more significant variations in T levels. The most considerable differences in T levels were observed in men younger than 30 years. There were no predictors of the magnitude of the T decrease in the afternoon. STRENGTHS AND LIMITATIONS: Strengths of the study include the number of subjects and the use of liquid chromatography-tandem mass spectrometry for T measurement. Limitations include failure to measure morning and afternoon T levels on the same day, the retrospective nature of the study, and a smaller sample size of patients younger than 30 years. CONCLUSION: In this study we found no strong link between age and daily T fluctuation, but we observed a decrease in the magnitude of variation with aging. The group experiencing the most significant decline in daily T had higher morning and consistently normal afternoon T levels.

The testis, eunuchs, and testosterone: a historical review over the ages and around the world.

INTRODUCTION: Testosterone therapy for men with testosterone deficiency is widely used, yet remains controversial. The rich and fascinating history of the testicles, including human castration, provides a valuable perspective on this important topic. OBJECTIVES: This study reviewed the history of testosterone from antiquity to the modern day. METHODS: Primary sources consisted of books and relevant articles, augmented by a MEDLINE search using the key words "testis," "testicles," "castration," "eunuchs," "testosterone," and "testicular function." RESULTS: An early scientific observation was that castration reduced sexual development and activity, originating with domestication of animals approximately 10 000 years ago. Human castration appears in ancient Egyptian mythology more than 4000 years ago, in Greek mythology from 8th century BCE, and in the Bible. The history of eunuchs in China spanned 2000 years, beginning with the Hsia dynasty (2205-1766 BCE). The concept that the testicles produced some factor responsible for male sexual development and behavior was thus known throughout the world since the beginning of recorded history. Testosterone was isolated and synthesized in 1935 and was soon available as a treatment. Multiple benefits of testosterone therapy were apparent by 1940. Recent large, controlled testosterone studies have conclusively demonstrated sexual and general health benefits, with a strong safety profile. CONCLUSION: Testosterone has been a known substance for <1% of the historical timeline, yet knowledge that the testes were responsible for male sexual development and behavior has been known since the beginning of recorded history. Today, modern evidence has demonstrated the importance of normal levels of testosterone for general health as well as sexual function and desire. Yet, testosterone therapy remains controversial. We believe this historical review provides a helpful perspective on this age-old issue.

The association between testosterone deficiency and nocturia: Insights from The National Health and Nutrition Examination Survey data set.

AIMS: To examine the association between testosterone deficiency (TD) and nocturia in males, with specific attention to age and cardiovascular disease (CVD) comorbidity. METHODS: This cross-sectional study utilized the National Health and Nutrition Examination Survey (NHANES) data from 2011 to 2016, assessing 6137 adult male participants. TD was defined by a serum total testosterone (TT) concentration less than 300 ng/dL. Nocturia was determined based on participants' responses to a standard NHANES question regarding the frequency of urination during the night. RESULTS: The study observed a significant association between TD and nocturia (adjusted odds ratio [95% confidence interval] = 1.211 [1.060-1.384], p = 0.005). Moreover, a U-shape pattern was noted in the relationship between serum TT concentration and the relative odds of nocturia. Subgroup analysis revealed a robust correlation between TD and nocturia in those over 60 years old, and those with hypertension, dyslipidemia, and CVDs. CONCLUSION: Our findings suggest a positive correlation between TD and nocturia, particularly among elderly individuals with CVD. This association underscores the potential therapeutic significance of addressing TD in the management of nocturia. Furthermore, longitudinal studies are needed to establish a causal relationship between TD and nocturia.

Clinical evaluation and treatment in men with low testosterone levels and prostate cancer.

INTRODUCTION: A high prevalence of low testosterone levels has been reported in men with prostate cancer. The use of testosterone therapy in men with a history of prostate cancer is still controversial, and there is uncertainty regarding the management of these patients. METHODS: We analyzed the European and American guidelines on this topic and presented the clinical experience in the management of patients with low testosterone levels and a history of prostate cancer in one of the world's leading cancer centers. RESULTS: According to the published evidence to date, testosterone therapy in men with prostate cancer does not increase the risk of prostate cancer recurrence in the short and medium term, but there is a lack of data on the long term. Symptomatic men with low testosterone levels who are candidates for this therapy need a thorough clinical evaluation before commencing testosterone therapy. Evaluation of prostate cancer history including type of treatment administered, pathologic stage of prostate cancer and prostate specific antigen should be requested before and during testosterone treatment to assess its trend. CONCLUSION: Prostate-specific antigen should remain undetectable after radical prostatectomy or stable after radiotherapy. Otherwise, it would be a sign of uncontrolled prostate cancer, and the patient may require cessation of testosterone therapy and referral to oncology for further evaluation.

Research trends in testosterone deficiency and management: A bibliometric analysis approach to quality improvement in urology resident education.

INTRODUCTION: Previous work has demonstrated a deficiency in urology resident education when it comes to andrology and male infertility. We analyzed the top 100 most frequently cited and influential articles published on testosterone deficiency and its associated therapy, allowing trainees and clinicians to review and understand the characteristics of impactful literature for self-directed learning purposes. METHODS: The ISI Web of Knowledge database was used to find articles on testosterone deficiency, hypogonadism, and replacement therapies. Relevant, peer-reviewed, English articles were included. Article details, including title, citation count, publication year, and more, were gathered. Articles were classified based on content (e.g. clinical outcomes, anatomy, and trends) using defined criteria. RESULTS: The top 300 most cited were reviewed with 100 included. The most cited article had 774 citations, averaging 234 in the top 100. Publication years had peaks in 2003-2004 and 2006-2007. The US led in publications (56), followed by England (16), Germany (14), and Italy (13). Common affiliations included US Department of Veteran Affairs, Veterans Health Administration, RIC Research Education Clinical Center, and University of California System. Articles were categorized as LOE 2 (47), LOE 1 (22), and LOE 5 (21). Articles focused on clinical outcomes (71.7%), anatomy/biomechanics/physiology (14.1%), clinical guidelines (8.1%), and screening (4%). The "Journal of Clinical Endocrinology & Metabolism" published 26 of the top 100 cited articles. CONCLUSIONS: This analysis highlights influential articles regarding testosterone deficiency and management. The discussed articles have significant clinical and therapeutic implications for the practicing urologist which may bolster deficits in current resident education.

Testosterone replacement therapy: association with mortality in high-risk patient subgroups.

OBJECTIVES: We describe studies determining the association between testosterone therapy (TTh) and mortality. MATERIALS & METHODS: We used a registry database of 737 men with adult-onset testosterone deficiency defined as presenting with low serum total testosterone (TT) levels ≤12.1 nmol/L and associated symptoms over a near 10-year follow-up. We compared associations between testosterone undecanoate (TU), cardio-metabolic risk factors and mortality using non-parametric statistics followed by separate Cox regression models to determine if any association between TU and morality was independent of age and cardio-metabolic risk factors. Finally, the association between TU and mortality was studied in men stratified by cardio-metabolic risk. RESULTS: During a median follow-up interquartile range (IQR) of 114 (84-132) months, 94 of the 737 men died. TU (ref: non-treatment) was associated with mortality; hazard ratio = 0.23, 95% confidence intervals = 0.14-0.40. Cox's regression models showed the above association to be independent of baseline age, waist circumference, hemoglobin A1c, lipids, blood pressure, smoking, and type 2 diabetes. These variables remained associated with mortality. We finally stratified the men by the high-risk baseline variables and established that the association between mortality and TU was only evident in men at higher risk. A possible explanation could lie with the "law of initial value," where greater improvements are evident following treatment in patients with worse baseline values. CONCLUSIONS: This study with long follow-up confirms that TTh is associated with lower mortality in men with adult-onset TD. This association was evident only in men with greater cardio-metabolic risk factors who demonstrated greater benefit.

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.