Effect of varicoceles on spermatogenesis.

Varicoceles are dilated veins within the spermatic cord and a relatively common occurrence in men. Fortunately, the large majority of men are asymptomatic, however, a proportion of men with varicoceles can suffer from infertility and testosterone deficiency. Sperm and testosterone are produced within the testis, and any alteration to the testicular environment can negatively affect the cells responsible for these processes. The negative impact of varicoceles on testicular function occurs mainly due to increased oxidative stress within the testicular parenchyma which is thought to be caused by scrotal hyperthermia, testicular hypoxia, and blood-testis barrier disruption. Management of varicoceles involves ligation or percutaneous embolization of the dilated veins. Repair of varicoceles can improve semen parameters and fertility, along with serum testosterone concentration. In this review, we discuss the pathophysiology of varicoceles, their impact on testicular function, and management.

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.

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.

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.

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 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.

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.

Effects of testis testosterone deficiency on gene expression in the adrenal gland and skeletal muscle of ducks.

1. Testosterone has an anabolic effect on skeletal muscle. The testes produce most of the testosterone in vivo, while the adrenal glands contribute smaller amounts. When testis testosterone is deficient the adrenal gland increases steroid hormone synthesis, which is referred to as compensatory testicular adaptation (CTA).2. To reveal the effects of testis testosterone deficiency on adrenal steroid hormones synthesis and skeletal muscle development, gene expression related to adrenal steroid hormones synthesis and skeletal muscle development were determined by RNA-seq.3. The results showed that castrating male ducks had significant effects on their body weight but no significant impact on cross-sectional area (CSA) or density of pectoral muscle fibres. In skeletal muscle protein metabolism, expression levels of the catabolic gene atrogin1/MAFbx and the anabolic gene eEF2 were significantly higher, with concomitant increases after castration. The adrenal glands' alteration of the steroid hormone 11ß-hydroxylase (CYP11B1) was significantly lower following castration.4. Expression pattern analysis showed that the adrenal glands' glucocorticoid receptor (NR3C1/GR) had a potential regulatory relationship with the skeletal muscle-related genes (Pax7, mTOR, FBXO32, FOXO3, and FOXO4).5. The data showed that castration affected muscle protein metabolism, adrenal steroid and testosterone synthesis. In addition, it was speculated that, after castration, steroid hormones produced by the adrenal gland could have a compensatory effect, which might mediate the changes in skeletal muscle protein metabolism and development.

[The results of the multicenter prospective comparative study of Androgel in men with endogenous testosterone deficiency and lower urinary tract symptoms, associated with benign prostate hyperplasia (POTOK)].

AIM: To evaluate the efficacy and safety of using Androgel in men with endogenous testosterone deficiency and lower urinary tract symptoms (LUTS), associated with benign prostatic hyperplasia (BPH) in routine clinical practice. MATERIALS AND METHODS: The multicenter, prospective, comparative study "POTOK" included 500 patients aged over 50 years with biochemical signs of testosterone deficiency (morning total testosterone concentration <12.1 nmol/l) and LUTS/BPH (International Prostatic Symptoms Score [IPSS] score of 8-19). The recruitment and monitoring of patients was carried out in 2022 in 40 clinics in Russia. Depending on the therapy, all patients were divided into two groups. The physician's decision to prescribe a specific drug (according to the approved patient information leaflet), as well as the subsequent follow-up scheme and therapy, was made a priori and independently of patient. In the first group (n=250) alpha-blockers and Androgel were prescribed, while in the second group (n=250) patients received monotherapy with alpha-blockers. The follow-up duration was 6 months. The efficiency of the therapy was evaluated after 3 and 6 months according to IPSS, symptoms of androgen deficiency (AMS and IIEF scores), uroflowmetry (peak flow rate, total urination volume), ultrasound study (postvoid residual and prostate volume). Safety was assessed by the total number of adverse events, stratified by severity and frequency. Statistical analysis was carried out using IBM SPSS 26.0. RESULTS: According to the primary end-point (IPSS score), there were significant differences between groups 1 and 2 after 3 months (11 vs. 12 points, p=0.009) and 6 months of therapy (9 vs. 11 points, p<0.001). There were also significant differences in the severity of symptoms of androgen deficiency after 3 and 6 months of therapy according to AMS score of 35 vs. 38 points (p<0.001) and 28 vs. 36 points (p<0.001), respectively. According to IIEF, all domains (erectile and orgasmic functions, libido, sexual satisfaction with and general satisfaction) were better in group 1 (p<0.001). After 6 months, uroflowmetry values also differed. In group 1 Qmax was 16 ml/s compared to 15.2 ml/s in group 2 (p=0.004); postvoid residual was 10 ml vs. 15.5 ml, respectively (p=0.001). The prostate volume in group 1 after 6 months of treatment was significantly lower (39.5 cc) compared with group 2 (43.3 cc; p=0.002). During the study, 18 mild AEs, 2 moderate AEs, and 1 severe AE were identified without significant differences between the groups (p>0.05). CONCLUSION: The results of study "POTOK" showed greater efficacy and comparable safety of alpha-blockers in combination with Androgel compared with monotherapy with alpha-blockers in men with LUTS/BPH and endogenous testosterone deficiency in routine clinical practice. The increase in serum testosterone concentrations to normal values in patients with age-related hypogonadism favorably influence on the severity of LUTS and the potentiate the effect of the standard monotherapy with alpha-blockers.

The Relationship Between PSA and Total Testosterone Levels in Men With Prostate Cancer.

BACKGROUND: Prostate-specific antigen (PSA) secretion is a testosterone (T) dependent process. Published data suggest that a low T level is an independent predictor of higher-grade prostate cancer (PC). AIM: To evaluate the relationship between T and PSA in patients with PC. METHODS: All men diagnosed with PC with a recorded pre-treatment total T level measurement were included in this analysis. We analyzed demographic, clinical, and pathological data. Patients were stratified according to pretreatment PSA levels: <2 ng/mL, 2-4 ng/mL, >4 ng/mL. Low T was defined as total T < 10.4 nmol/L (300 ng/dL), very low T < 6.9 nmol/L (200 ng/dL). OUTCOMES: T levels by PSA groups according to the PC pathology. RESULTS: In this retrospective study, mean patient age was 61 years among 646 men. The distribution by PSA group was: 8% (<2), 17% (2-4), and 76% (>4). The mean T level across the entire cohort was 13 nmol/L (374 ng/dL). Overall, 30% had a T level < 10.4 nmol/L (300 ng/dL). The mean total T level by PSA group was: <2 ng/mL, 7 nmol/L (206 ng/dL); 2-4 ng/mL, 13 nmol/L (362 ng/dL); >4 ng/mL, 14 nmol/L (393 ng/dL), P < .001. PSA <4 ng/mL was a significant predictor of low T in men with PC GS ≥8. PSA <2 ng/mL was a significant predictor of very low T independent of the PC pathology. CLINICAL IMPLICATIONS: These findings suggest that clinicians should consider measuring T levels when a patient diagnosed with PC GS ≥8 and PSA level <4 ng/mL, and for each patient with PSA level <2 ng/mL independent of the PC pathology. STRENGTHS & LIMITATIONS: Our study has several strengths including (i) inclusion of a large population of men, (ii) use of a database which is audited and reviewed for accuracy annually, and (iii) use of an accurate T assay (LCMS). Nonetheless, there are limitations: (i) the subjects of the study are from a single institution, and (ii) we did not measure free T levels. CONCLUSION: In men with PC with GS ≥8, PSA level <4 ng/mL predicts low T. PSA <2 ng/mL predicts very low T independent of the PC pathology. Flores JM, Bernie HL, Miranda E, et al. The Relationship Between PSA and Total Testosterone Levels in Men With Prostate Cancer. J Sex Med 2022;19:471-478.

Practice Comparison and Cost Analysis of Direct-to-Consumer Telemedicine Platforms Offering Testosterone Therapy.

BACKGROUND: Direct-to-consumer telemedicine platforms have expanded their reach to include services for the evaluation and treatment of testosterone deficiency. AIM: We aim to (i) evaluate the treatment practices and costs associated with receiving testosterone therapy through direct-to-consumer telemedicine platforms; (ii) compare these practices to the American Urological Association guidelines; and (iii) compare the cost of receiving similar care at a tertiary center. METHODS: Google was queried to identify telemedicine platforms offing testosterone therapy. Websites were analyzed for information regarding the initial consultation, initial laboratory evaluation, follow up, treatment monitoring regimen, and associated costs of receiving testosterone therapy. The costs for similar services at a tertiary care center were estimated using a single institution's online cost estimator for a patient with no insurance, private insurance, or Medicare. OUTCOMES: Evaluation and treatment practices of each platform were compared to the American Urological Association guidelines, and a cost analysis was completed for the cost of (i) undergoing an initial evaluation, and (ii) receiving 12 months of treatment through each platform and at a tertiary center. RESULTS: Three online platforms met inclusion criteria: Hone, Regenex Health, and TRT Nation. The initial evaluation and follow up of patients on TTh were similar between the online platforms and practice guidelines. The costs of the initial consultation were lowest for the patient with Medicare at a tertiary center and via the telemedicine platforms. Conversely, the cost of 12 months of intramuscular testosterone treatment was highest via the telemedicine platforms, ranging from $1,586 to $4,200, as compared to the tertiary center, which ranged from $134.01 to $1,333.04 with varying insurance models. Costs of ongoing treatment with transdermal testosterone are similarly higher via DTC platforms. CLINICAL IMPLICATIONS: Patients with private insurance or Medicare should be counseled that ongoing treatment through telemedicine platforms will likely incur a greater cost than receiving such care at a tertiary center that can utilize insurance coverage. STRENGTHS & LIMITATIONS: Practice and cost comparisons include accurate, up-to-date information based on each platform's website. Limitations include the analysis of only three telemedicine platforms, and the ability to describe only the information provided on each website. In addition, cost estimates for the tertiary center only include a single type of private and public insurance, limiting generalizability. CONCLUSION: This observational study indicates that direct-to-consumer telemedicine platforms are largely following practice guidelines in the evaluation and treatment of testosterone, however, there is a high cost associated with ongoing treatment. Jesse E, Sellke N, Rivero M-J, et al. Practice Comparison and Cost Analysis of Direct-to-Consumer Telemedicine Platforms Offering Testosterone Therapy. J Sex Med 2022;19:1608-1615.

Luteinizing Hormone Suppression Profiles in Men Treated With Exogenous Testosterone.

BACKGROUND: Due to the negative feedback mechanism involved in the hypothalamic-pituitary-gonadal axis, testosterone therapy (TTh) may result in suppression of luteinizing hormone (LH) secretion, but clinical experience demonstrates the level of LH suppression is variable. AIM: We sought to define the relationship between TTh and LH levels, specifically predictors of LH suppression in men on TTh. METHODS: We performed a retrospective analysis of a prospectively maintained database of patients with testosterone deficiency (TD) treated with TTh. Patient demographic and clinical data including vascular risk factor (VRF) status were collected. Serum total T and LH levels before TTh and after ≥3 months (m) were recorded. LH suppression was defined as serum LH level <1.0 IU/ml. MAIN OUTCOME MEASURES: Predictors of LH suppression were searched though a series of logistic regression models assessing suppression status at the final observation, and then a series of Cox proportional hazards models assessing time to first suppression were performed. RESULTS: A total of 227 patients with mean age of 58±14 years at time of TTh initiation were included in our analysis. Just under half of subjects received transdermal T as the only modality (n = 101, 44%), while one third (n = 77, 34%) received intramuscular only, and the remainder (n = 49, 22%) received both modalities during follow-up. The mean baseline LH level was 10 ± 12 IU/ml. The percent of men who had baseline LH level above 1 IU/ml and at any given point of TTh was 84% and 78%, respectively, thus 22% of men had suppressed LH levels on TTh considering the definition of LH <1 IU/ml. Most men (73%) had a suppressed LH level of <1 IU/ml at least once during follow-up. In the final adjusted model for LH suppression, intramuscular route (OR = 2.44), baseline LH (OR = 0.94), estradiol (OR = 1.05) remained significant. CLINICAL IMPLICATIONS: LH suppression profiles may be relevant for dose titration during TTh and perhaps to minimize testicular atrophy. STRENGTHS & LIMITATIONS: A strict definition for TD was applied using LCMS for T measurements and patients had long-term follow-up. CONCLUSION: While 73% of patients had at least one LH <1 IU/ml during TTh, only 22% maintained suppressed throughout the treatment. Miranda EP, Schofield E, Matsushita K, et al. Luteinizing Hormone Suppression Profiles in Men Treated With Exogenous Testosterone. J Sex Med 2022;19:1359-1365.

Lower urinary tract symptoms are associated with clinically relevant depression, anxiety, and stress symptoms.

OBJECTIVES: To investigate the correlation between lower urinary tract symptoms (LUTS), erectile dysfunction (ED), and testosterone deficiency (TD) with depressive, stress, and anxiety symptoms. MATERIAL AND METHODS: From October 2019 to March 2020, 113 males were included. Inclusion criteria: age 40-75, no clinical suspicion of prostate cancer, no serious cardiovascular comorbidities. All patients completed a set of questionnaires: International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5), and Depression Anxiety Stress Scales (DASS-21). RESULTS: Median age was 62 years (range 40-74), mean IPSS score was 10.94 (SD 7.75), mean IIEF-5 score 13.12 (SD 7.08), and mean DASS-21 score 11.35 (SD 8.24). According to DASS-21 subscales, 28 (24.8%) patients had depressive symptoms, 25 (22.1%) anxiety symptoms, and 25 (22.1%) stress symptoms. Depression was associated with LUTS (14.5 vs. 8 score, p = .002). Similarly, stress symptoms were associated with LUTS (IPSS 15 vs. 7 score, p = .0001) and with ED (IIEF-5 5 vs. 15 score, p = .01). Positive Spearman's rho correlations between LUTS and all three, depression, anxiety, and stress symptoms were found (p values <.001). CONCLUSIONS: LUTS is associated with depression, anxiety, and stress symptoms. Screening for these symptoms could help with individual counseling and management.

A simple questionnaire for the detection of testosterone deficiency in men with late-onset hypogonadism.

The Aging Males' Symptoms (AMS) score, developed to screen for late-onset hypogonadism (LOH), contains 17 questions regarding mental, physical, and sexual parameters. In the Japanese guidelines, a free testosterone (FT) <8.5 pg/mL is recommended for testosterone treatment. However, previous studies have shown no correlation between total AMS scores and testosterone concentration. We aimed to develop a better questionnaire for the detection of testosterone deficiency in men, for the diagnosis of LOH. In 234 Japanese men, aged 40-64 years, we analyzed the relationships of AMS with serum total testosterone (TT), FT, calculated FT (cFT), and calculated bioavailable testosterone (cBT), and identified useful questions for the detection of testosterone deficiency. Four scores, a decrease in muscular strength, a decrease in ability to perform sexually or the frequency, a decrease in the number of morning erections, and a decrease in sexual desire/libido, were negatively associated with two or more of the above four testosterone parameters, and the sum of these four scores (named the selective score) correlated with TT and cFT, independent of age. Statistical analysis revealed an association between insulin resistance and testosterone deficiency, and a higher selective score in smokers than non-smokers. Cubic function model analysis and logistic regression analysis revealed that selective scores ≥10 corresponded with the testosterone concentrations recommended for the diagnosis of LOH, including FT <8.5 pg/mL, independent of age, insulin resistance, and smoking. Thus, the selective score represents a simple and useful means for screening of testosterone deficiency in Japanese men, as an indicator of LOH.

[Evolution of views on the etiology and pathogenesis of lower urinary tract symptoms for men].

The review article in the format of a "Lecture for Doctors" examines the evolution of terminology reflecting various disorders of urination and understanding their etiology and pathogenesis from a methodological and historical point of view. Symptoms of the lower urinary tract (LUTS) is a new term that replaced the term "Dysuria" that previously existed in the literature and suggests the allocation of various groups of symptoms depending on the violation of key functions of the bladder, which greatly facilitates obtaining reliable information about the state of urination in a particular patient. However, for a long time, LUTS were identified exclusively with urological pathology. Thanks to the fundamental research of recent decades, it has become obvious that LUTS is an interdisciplinary problem involving various specialists in the process of diagnosis and correction. One of the current trends in the study of the urination pathophysiology is the influence of systemic hormonal and metabolic disorders in men, which are considered as independent factors of the LUTS. The role of testosterone deficiency in the pathogenesis of LUTS is highlighted and the safety and effectiveness of testosterone replacement therapy (TRT) in hypogonadal men with LUTS is shown.

Amodiaquine promotes testosterone production and de novo synthesis of cholesterol and triglycerides in Leydig cells.

Testosterone is a hormone essential for male reproductive function. It is produced primarily by Leydig cells in the testicle through activation of steroidogenic acute regulatory protein and a series of steroidogenic enzymes, including a cytochrome P450 side-chain cleavage enzyme (cytochome P450 family 11 subfamily A member 1), 17α-hydroxylase (cytochrome P450 family 17 subfamily A member 1), and 3ß-hydroxysteroid dehydrogenase. These steroidogenic enzymes are mainly regulated at the transcriptional level, and their expression is increased by the nuclear receptor 4A1. However, the effect on Leydig cell function of a small molecule-activating ligand, amodiaquine (AQ), is unknown. We found that AQ effectively and significantly increased testosterone production in TM3 and primary Leydig cells through enhanced expression of steroidogenic acute regulatory protein, cytochome P450 family 11 subfamily A member 1, cytochrome P450 family 17 subfamily A member 1, and 3ß-hydroxysteroid dehydrogenase. Concurrently, AQ dose-dependently increased the expression of 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in the cholesterol synthesis pathway, through induction of the transcriptional and DNA-binding activities of nuclear receptor 4A1, contributing to increased cholesterol synthesis in Leydig cells. Furthermore, AQ increased the expression of fatty acid synthase and diacylglycerol acyltransferase and potentiated de novo synthesis of fatty acids and triglycerides (TGs). Lipidomics profiling further confirmed a significant elevation of intracellular lipid and TG levels by AQ in Leydig cells. These results demonstrated that AQ effectively promotes testosterone production and de novo synthesis of cholesterol and TG in Leydig cells, indicating that AQ may be beneficial for treating patients with Leydig cell dysfunction and subsequent testosterone deficiency.

Androgen-dependent miR-125a-5p targets LYPLA1 and regulates global protein palmitoylation level in late-onset hypogonadism males.

Late-onset hypogonadism (LOH) is defined as a clinical and biochemical syndrome with multiple symptoms caused by testosterone deficiency in aging males. An in-depth exploration of the molecular mechanism underlying LOH development is insufficient. We previously identified miR-125a-5p as a dysregulated microRNA in LOH patients and potential diagnostic biomarker for LOH. The present study demonstrated that plasma miR-125a-5p was upregulated after testosterone supplementation in both LOH patients and castrated mice, and positively associated with the testosterone concentrations, suggesting direct regulation of miR-125a-5p expression by testosterone. Androgen response element in the promoter of miR-125a-5p was subsequently identified. Target gene screening and confirmation verified that LYPLA1, encoding acyl-protein thioesterase 1 which catalyzed protein depalmitoylation process, was a target gene of miR-125a-5p. Furthermore, in cells cultured with testosterone deprivation and organs from castrated mice, testosterone deficiency led to decreased global protein palmitoylation level. In aging males, global protein palmitoylation in peripheral blood showed a notable decline in LOH patients contrast to the normal elderly males. And the palmitoylation level was positively correlative with serum testosterone concentrations. Our results suggested that testosterone could regulate global palmitoylation level through miR-125a-5p/LYPLA1 signaling pathway. Given that protein palmitoylation is pivotal for protein function and constitutes the pathogenesis of various diseases, testosterone/miR-125a-5p/LYPLA1 may contribute to the molecular mechanism underlying multiple symptoms caused by testosterone deficiency in LOH patients, and aberrant global palmitoylation could be a potential biomarker for LOH.

Testosterone deficiency accelerates early stage atherosclerosis in miniature pigs fed a high-fat and high-cholesterol diet: urine 1H NMR metabolomics targeted analysis.

To gain insights into the role of testosterone in the development of atherosclerosis and its related metabolic pathways, we applied a proton nuclear magnetic resonance (1H NMR)-based metabolomics approach to investigate urine metabolic profiles in miniature pigs fed a high-fat and high-cholesterol (HFC) diet among intact male pigs (IM), castrated male pigs (CM) and castrated male pigs with testosterone replacement (CMT). Our results showed that testosterone deficiency significantly increased atherosclerotic lesion areas, intima-media thickness, as well as serum lipid levels in the CM pigs. Moreover, seventeen significantly changed metabolites were identified in both IM vs. CM and CMT vs. CM groups. Among these, seven were shared between the two comparative groups and were all significantly reduced in the urine of the CM group but rescued in the CMT group. In addition, the correlation analysis demonstrated that several metabolites, including niacinamide, myo-inositol, choline and 3-hydroxyisovalerate, were negatively correlated with atherosclerotic lesion areas. Our study demonstrated that testosterone deficiency accelerated early AS formation in HFC diet-fed pigs, which involved several metabolites predominantly related to lipid metabolism, inflammation, oxidative stress and endothelial disorders. Our results reveal potential pathways in the pathogenesis of atherosclerosis caused by testosterone deficiency and HFC diet.

Recommendations on the diagnosis, treatment and monitoring of testosterone deficiency in men.

The relative proportional increase of the elderly population within many countries will become one of the most significant social transformations of the twenty-first century and, for the first time in history, persons aged 65 or above outnumbered children under five years of age globally. One in four persons living in Europe and Northern America will be aged 65 or over. One of the goals of ISSAM is to raise awareness of the special health needs of older men. Since a significant number of aging men will eventually become testosterone deficient, the Hypogonadism panel of ISSAM updates its guidelines.

Low free testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors.

Aim: We investigated whether low plasma free testosterone (FT) levels could predict cardiovascular events (CVE) in Japanese men with coronary risk factors.Methods: Male patients with classical coronary risk factors who had undergone serum FT testing were enrolled. New incidences of CVE were retrospectively investigated among all eligible participants based on their medical records.Results: Overall, 466 male outpatients with coronary risk factors without a previous history of CVE were identified. Throughout the follow-up period (median = 92 months), 126 CVE occurred. The Kaplan-Meier survival analysis according to the tertiles of plasma FT levels revealed that patients with the lowest FT tertile (<6.5 pg/mL) had a higher likelihood of developing CVE than those with the highest tertile (>9.3 pg/mL) (p<.01). Multivariate analysis showed that increased frequency of CVE was observed with lower FT tertiles, independent of other coronary risk factors, with hazard ratios of 0.617 (95% CI, 0.389-0.976; p=.030) and 0.524 (95% CI, 0.309-0.887; p=.016) for the second and highest tertile relative to the lowest FT tertile, respectively.Conclusion: Among Japanese men with coronary risk factors, a lower FT level was a predictor for the development of cardiovascular diseases independent of other coronary risk factors and age.