Bioavailable Testosterone Levels Research Articles

Cross-sectional analysis of sleep hours and quality with sex hormones in men

BackgroundReduced total hours of sleep and low quality of sleep have been suggested to be associated with low levels of male hormones. Few studies have examined the association between excessive sleep and male reproductive hormones.ObjectiveTo investigate the association of total hours of sleep and quality of sleep with serum levels of total, bioavailable and free testosterone (tT, bT and fT), sex hormone-binding globulin (SHBG) and dehydroepiandrosteron-sulfate (DHEAS).MethodsSerum levels of tT, SHBG and DHEAS were measured with immunoassays in a cross-sectional population-based study of 2095 males. bT and fT were calculated in accordance with Vermeulens method. Information on total hours of sleep and sleep quality was obtained by questionnaire. Linear regression was used to calculate hormones according to total hours of sleep and the results were expressed as β-estimates and 95% confidence intervals (CI). The adjustment in the multivariable models was constructed taking age, BMI, smoking, alcohol intake and physical activity into account.ResultsExcessive sleep (>9 h) compared to 7–9 h of sleep was significantly associated with lower tT, bT and fT, but not with SHBG or DHEAS, after multivariable adjustment. These significant associations were also found in our analyses with hormones as continuous variables but no associations were found in our general additive model analyses.ConclusionsIn this cross-sectional study in men, excessive sleep associated with lower levels of male reproductive hormones. Longitudinal studies are needed to determine the causal direction of the observed association between excessive sleep and lower male reproductive hormones levels.

Associations of sex hormone-binding globulin and testosterone with genome-wide DNA methylation

BackgroundLevels of sex hormone-binding globulin (SHBG) and the androgen testosterone have been associated with risk of diseases throughout the lifecourse. Although both SHBG and testosterone have been shown to be highly heritable, only a fraction of that heritability has been explained by genetic studies. Epigenetic modifications such as DNA methylation may explain some of the missing heritability and could potentially inform biological knowledge of endocrine disease mechanisms involved in development of later life disease. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we explored cross-sectional associations of SHBG, total testosterone and bioavailable testosterone in childhood (males only) and adolescence (both males and females) with genome-wide DNA methylation. We also report associations of a SHBG polymorphism (rs12150660) with DNA methylation, which leads to differential levels of SHBG in carriers, as a genetic proxy of circulating SHBG levels.ResultsWe identified several novel sites and genomic regions where levels of SHBG, total testosterone, and bioavailable testosterone were associated with DNA methylation, including one region associated with total testosterone in males (annotated to the KLHL31 gene) in both childhood and adolescence and a second region associated with bioavailable testosterone (annotated to the CMYA5 gene) at both time-points. We also identified one region where both SHBG and bioavailable testosterone in males in childhood (annotated to the ZNF718 gene) was associated with DNA methylation.ConclusionOur findings have important implications in the understanding of the biological processes of SHBG and testosterone, with the potential for future work to determine the molecular mechanisms that could underpin these associations.

Dysbalanced sex hormone status is an independent predictor of decompensation and mortality in patients with liver cirrhosis.

AimsEndocrinological abnormalities, including low testosterone levels, are prevalent in cirrhosis. We assessed sexual hormone status in regard to hemodynamic abnormalities and its impact on hepatic decompensation and survival.MethodsMales with cirrhosis were prospectively included in this study since 2010. Sexual hormones including bioavailable testosterone, total testosterone, luteinizing hormone, follicle‐stimulating hormone, prolactin, and sex hormone‐binding globulin as well as Child–Pugh score, Model for End‐stage Liver Disease (MELD) score, and hepatic venous pressure gradient were recorded. Sarcopenia was also assessed in patients with available computed tomography scans. Clinical follow‐up for hepatic decompensation, liver transplantation, and death was recorded until May 2017.ResultsOne hundred fourteen male cirrhotic patients were included: age 55 ± 9.4 years, MELD 13.5 (range, 7–20.7). Etiologies were alcoholic liver disease in 61(53.5%) patients, viral in 30 (26.3%) patients, and other in 23 (20.2%). Child–Pugh scores were A in 32 (28.1%) patients, B in 48 (42.1%), and C in 34 (29.8%). Levels of bioavailable testosterone and total testosterone decreased with advanced Child–Pugh score (P < 0.001 and P < 0.001) whereas prolactin increased (P = 0.002). Median bioavailable testosterone (0.8 ng/mL [0.1–2] vs. 1.68 ng/mL [0.07–2.65]; P = 0.004) and total testosterone (2.7 ng/mL [0.23–12.34] vs. 7 ng/mL [0.25–10]; P = 0.041) levels were lower in patients with severe portal hypertension (hepatic venous pressure gradient >12 mmHg). Median bioavailable testosterone (0.25 ng/mL [0.07–1.7] vs. 0.97 ng/mL [0.15–2.74)]; P = 0.017) and total testosterone levels (1.28 ng/mL [0.25–7.32] vs. 4.32 ng/mL [0.43–13.47]; P = 0.031) were significantly lower in sarcopenic patients. Median follow‐up was 13 months (0.2–75 months) and liver‐related events were recorded in 46 patients (40.4%; death, 31 [27.2%]). Low total testosterone was associated with an increased risk for hepatic decompensation and/or death, even after adjusting for Child–Pugh score, MELD, and other relevant factors (Child–Pugh score model: hazard ratio 2.503, 95% confidence interval, 1.214–5.157, P = 0.013; MELD model: hazard ratio 3.065, 95% confidence interval, 1.523–6.169, P = 0.002).ConclusionIn parallel to increasing severity of cirrhosis, levels of testosterone decline whereas prolactin levels increase. However, low testosterone levels are independently associated with a higher risk for hepatic decompensation and mortality.

Aggressiveness of Localized Prostate Cancer: the Key Value of Testosterone Deficiency Evaluated by Both Total and Bioavailable Testosterone: AndroCan Study Results.

Failure rates after first-line treatment of localized prostate cancer (PCa) treatment remain high. Improvements to patient selection and identification of at-risk patients are central to reducing mortality. We aimed to determine if cancer aggressiveness correlates with androgen levels in patients undergoing radical prostatectomy for localized PCa. We performed a prospective, multicenter cohort study between June 2013 and June 2016, involving men with localized PCa scheduled to undergo radical prostatectomy. Clinical and hormonal patient data (testosterone deficiency, defined by total testosterone (TT) levels < 300ng/dL and/or bioavailable testosterone (BT) levels < 80ng/dL) were prospectively collected, along with pathological assessment of preoperative biopsy and subsequent radical prostatectomy specimens, using predominant Gleason pattern (prdGP) 3/4 grading. Of 1343 patients analyzed, 912 (68%) had prdGP3 PCa and 431 (32%) had high-grade (prdGP4, i.e., ISUP ≥ 3) disease on prostatectomy specimens. Only moderate concordance in prdGP scores between prostate biopsies and prostatectomy specimens was found. Compared with patients with prdGP3 tumors (i.e., ISUP ≤ 2), significantly more patients with prdGP4 cancers had demonstrable hypogonadism, characterized either by BT levels (17.4% vs. 10.7%, p < 0.001) or TT levels (14.2% vs. 9.7%, p = 0.020). BT levels were also lower in patients with prdGP4 tumors compared to those with prdGP3 disease. Testosterone deficiency (defined by TT and/or BT levels) was independently associated with higher PCa aggressiveness. BT is a predictive factor for prdGP4 disease, and evaluating both TT and BT to define hypogonadism is valuable in preoperative assessment of PCa (AndroCan Trial: NCT02235142).

Association between serum levels of insulin-like growth factor-1, bioavailable testosterone, and pathologic Gleason score.

BackgroundWe evaluated the association between serum levels of insulin‐like growth factor‐1 (IGF‐1), bioavailable testosterone, and surgical Gleason score (GS).MethodsWe analyzed 793 patients who underwent radical prostatectomy and 272 men with negative prostate biopsy. Serum levels of IGF‐1 and testosterone were measured before surgery or biopsy.ResultsThe mean IGF‐1 levels of prostate cancer patients and men with a negative biopsy were 143.8 and 118.9 ng/mL, respectively (P < 0.001). Men with high serum IGF‐1 were more likely to have prostate cancer (highest vs lowest quartile, odds ratio [OR] = 3.35; P trend < 0.001). However, among men with prostate cancer, the mean IGF‐1 levels of those with low (GS ≤ 6), intermediate (GS = 7), and high surgical GS (GS ≥8) were 151.7, 144.1, and 132.9 ng/mL, respectively (P < 0.001). Using quartile analysis, high serum IGF‐1 levels were shown to be associated with a low risk of high surgical GS (OR = 0.464; P trend = 0.006). Serum bioavailable testosterone concentration was positively correlated with serum IGF‐1 level (r = 0.157, P < 0.001). High bioavailable testosterone level was also associated with a low risk of high surgical GS in patients without diabetes mellitus (OR = 0.569; P trend = 0.040). Among men with biopsy GS ≤ 3 + 4 (n = 460), upgrading to high surgical GS was more frequent in patients with low IGF‐1 level (≤116.0 ng/mL; 9.9%) or low bioavailable testosterone level (≤0.85 ng/mL; 9.3%) than in patients with normal IGF‐1 and bioavailable testosterone levels (2.6%; P = 0.004).ConclusionsSerum levels of IGF‐1 and bioavailable testosterone show inverse associations with high surgical GS. This suggests that high‐grade prostate cancer develops independently of these two substances.

Combination therapy with clomiphene citrate and anastrozole is a safe and effective alternative for hypoandrogenic subfertile men.

To assess the efficacy and safety of combination therapy with clomiphene citrate (CC) and anastrozole (AZ) for male hypoandrogenism. We identified patients treated with a combination of CC + AZ in the period 2014 to 2017. Data were gathered on patient characteristics and laboratory values at baseline. Total testosterone, bioavailable testosterone, oestradiol and testosterone:oestradiol ratio were measured before combination therapy (treatment with CC only) and at CC + AZ combination therapy follow-ups. Treatment side effects were recorded; prostatic-specific antigen and haematocrit levels were measured to assess safety after 6 months. As a secondary outcome, semen characteristics were compared at baseline and after at least 3 months of combination therapy when these data were available. Data were analysed using a paired t-test and Wilcoxon's signed-rank test. A total of 51 men were included, with a mean age of 35.4 ± 7.4 years and a mean body mass index of 35.0 ± 8.0 kg/m2 . After CC treatment, total testosterone, bioavailable testosterone, and oestradiol levels all significantly increased. AZ was added in all patients with hyperoestrogenaemia (oestradiol >50 pg/mL) or a testosterone:oestradiol ratio <10. CC + AZ therapy maintained therapeutic total testosterone and bioavailable testosterone levels while also normalizing oestradiol levels and testosterone:oestradiol ratio. Eleven patients experienced side effects: anxiety/irritability, n = 5; decreased libido, n = 4; elevated (>54%) haematocrit, n = 2. Combination therapy with CC + AZ is an effective and safe alternative for patients with elevated oestradiol level or low testosterone:oestradiol ratio.

Mitochondria, glycogen, and lipid droplets in skeletal muscle during testosterone treatment and strength training: a randomized, double-blinded, placebo-controlled trial.

Low testosterone levels in aging men are associated with insulin resistance. Mitochondrial dysfunction, changes in glycogen metabolism, and lipid accumulation are linked to insulin resistance in skeletal muscle. In this randomized, double-blinded, placebo-controlled study, we investigated the effects of six-month testosterone replacement therapy (TRT) and strength training (ST) on mitochondrial, glycogen, and lipid droplet (LD) content in skeletal muscle of aging men with subnormal bioavailable testosterone (BioT) levels. Mitochondrial, glycogen, and LD volume fractions in muscle biopsies were estimated by transmission electron microscopy. Insulin sensitivity (insulin-stimulated Rd) and body composition were assessed by euglycemic-hyperinsulinemic clamp and dual X-ray absorptiometry, respectively. TRT significantly increased total testosterone levels, BioT, and lean body mass (LBM) (p<0.05), whereas percent body fat decreased (p<0.05), and insulin sensitivity was unchanged. Baseline mitochondrial volume fraction correlated inversely with percent body fat (ρ=-0.43; p=0.003). Δ-mitochondrial fraction correlated positively with Δ-total testosterone (ρ=0.70; p=0.02), and Δ-glycogen fraction correlated inversely with Δ-LBM (ρ=-0.83; p=0.002) during six-month TRT, but no significant changes were observed in mitochondrial, glycogen, and LD volume fractions during TRT and ST. In conclusion, in this exploratory small-scale study, the beneficial effects of six-month TRT on total testosterone, LBM, and percent body fat were not followed by significant changes in fractions of mitochondria, glycogen, or lipid in skeletal muscle of aging men with lowered testosterone levels. Six-month ST or combined three-month ST+TRT did not change intramyocellular mitochondria, glycogen, and LD fractions compared to placebo. However, further studies with a larger sample size are needed.

Statin Therapy and Serum Testosterone in Men with Type 2 Diabetes

There is a high prevalence of hypogonadism in men with type 2 diabetes. Statins could potentially decrease testosterone levels by reducing the availability of cholesterol for androgen synthesis. In this study we compared testosterone levels and hypogonadal symptoms with statin use in men with type 2 diabetes. PATIENTS AND METHODS Total testosterone, sex hormone–binding globulin (SHBG), and estradiol were measured by an enzyme-linked immunosorbent assay. Bioavailable testosterone was measured by the modified ammonium sulfate precipitation method. Free testosterone was calculated using Vermeulen's formula. Symptoms of hypogonadism were assessed using the Androgen Deficiency in the Aging Male questionnaire. RESULTS Statins were associated with lower total testosterone and a trend toward lower SHBG compared with untreated patients. Bioavailable testosterone, free testosterone, estradiol, and hypogonadal symptoms were not affected. Atorvastatin was associated with reduced total testosterone and a trend toward reduced SHBG compared with no treatment, and there was a dose-response effect with the lowest levels of total testosterone seen in men treated with ≥20 mg atorvastatin .Simvastatin use was not associated with significant reductions in testosterone or SHBG levels. CONCLUSION Assessing androgen status using total testosterone in men with type 2 diabetes treated with statins, particularly atorvastatin, may potentially lead to diagnostic error. Levels of bioavailable testosterone or free testosterone are recommended for the assessment of hypogonadism in this group if total testosterone levels are borderline.

The relationship between lipoprotein-associated phospholipase A2 with cardiovascular risk factors in testosterone deficiency.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) which is believed to play a role in atherosclerotic inflammatory process due to its function in hydrolysis of phospholipids and release of pro-inflammatory products, is considered as a novel biomarker for vascular risk. In this study we aimed to investigate the alterations in Lp-PLA2 and its relationship with other cardiovascular risk factors in patients with testosterone deficiency. Forty hypogonadic male and 30 healthy male aged between 18-50 years were enrolled in this study. Height-weight, waist-to-hip circumference, body mass index (BMI) blood pressure, and body fat measurements were performed in all subjects. Blood glucose, albumin, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, high sensitive C-reactive protein (hs-CRP), apo-A1, apo-B, fibrinogen, insulin, total testosterone, sex hormone binding globulin (SHBG), small dense low-density lipoprotein (sd-LDL), paraoxonase 1, oxidized low-density lipoprotein (ox-LDL) and Lp-PLA 2 values were measured. Free and bioavailable testosterone levels were calculated. Data management was carried out with the statistical program SAS Version 9.2. Statistical evaluations were performed using Analysis of Variance (ANOVA), Kruskal-Wallis test, Wilcoxon test, correlation analysis and chi-square analysis. P values <0.05 were considered statistically significant. In patients with hypogonadism, significant increase in Lp-PLA2 levels were accompanied with risk factors of atherosclerosis, such as increase in total cholesterol, apo-B, sd-LDL, weight, BMI, body fat percentage, and decrease in paraoxonase 1 levels. Although the differences were not significant, similarly ox-LDL, hs-CRP, triglyceride, LDL-cholesterol levels were found to be higher in patients with hypogonadism compared to the control group. The mean level of Lp-PLA2 was the highest when compared with the group of secondary hypogonadism with the lowest testosterone level. Our study has demonstrated that the testosterone deficiency increases cardiovascular risk via its effects on lipid metabolism and Lp-PLA2 can be used to assess this risk.

Current smoking is associated with a larger waist circumference and a more androgenic profile in young healthy women from high-risk breast cancer families

The purpose was to elucidate the interplay between current smoking, anthropometric measurements, and endogenous hormone levels in women ≤ 40 years. Questionnaires on lifestyle and reproductive factors were completed by 269 healthy women from high-risk breast cancer families between 1996 and 2006 in Sweden. Blood samples for analyses of plasma testosterone, estradiol, androstenedione, sex hormone-binding globulin, and body measurements were obtained 5–10 days before predicted onset of the next menstrual period. Women without smoking status, who were currently breastfeeding, or using hormonal contraception other than combined oral contraceptives (OCs) were excluded (n = 27). Current smokers (n = 57) had larger waist circumference (adjp = 0.004) and waist-to-hip ratio (WHR) (adjp = 0.007) than non-smokers (n = 185). In non-OC users, adjusted mean androstenedione levels were higher in current smokers compared with non-smokers (10.3 vs. 8.6 nmol/L; adjp = 0.0002). While in current OC users estradiol levels were higher in smokers compared with non-smokers (22.5 vs. 17.4 pg/mL; adjp = 0.012). In multivariable models, WHR was associated with both current smoking (adjp ≤ 0.016) and higher levels of androstenedione (adjp = 0.05) or bioavailable testosterone (adjp = 0.001). Among non-OC users, a more androgenic profile was observed in current smokers compared with non-smokers, but not in current OC users. Irrespective of OC use, current smoking was associated with increased waist circumference.

Complex Association of Sex Hormones on Left Ventricular Systolic Function: Insight into Sexual Dimorphism

Normal values of left ventricular ejection fraction (LVEF) and absolute values of global longitudinal strain (GLS) are lower in men than in women. Data concerning the association of sex hormone levels on these left ventricular systolic function surrogates are scarce. The aim of this study was to determine the association of sex hormones with systolic left ventricular function in healthy subjects and patients with congenital adrenal hyperplasia (CAH) as a model of testosterone dysregulation. Eighty-four adult patients with CAH (58 women; median age, 27years; interquartile range, 23-36years) and 84 healthy subjects matched for sex and age were prospectively included. Circulating concentrations of sex hormones were measured within 48hours of echocardiography with assessment of LVEF and left ventricular longitudinal, radial, and circumferential strain. LVEF and GLS were higher in healthy women than in healthy men (63.9±4.2% vs 60.9±5.1% [P<.05] and 20.0±1.9% vs 17.9±2.4% [P<.001], respectively), while there was no difference in LVEF or GLS between women and men with CAH (63.9±4.5% vs 63.0±4.6% [P= NS] and 19.4±2.2% vs 18.3±1.8% [P= NS], respectively). Bioavailable testosterone levels were higher in women with CAH than in female control subjects (0.08ng/mL [interquartile range, 0.04-0.14ng/mL] vs 0.16ng/mL [interquartile range, 0.04-0.3ng/mL], P<.001) and lower in men with CAH than in male control subjects (2.3ng/mL [interquartile range, 1.3-3ng/mL] vs 2.9ng/mL [interquartile range, 2.5-3.4ng/mL], P<.05). In men, LVEF and GLS were negatively correlated with bioavailable testosterone levels (r=-0.3, P≤.05, and r=-0.45, P<.01, respectively), while midventricular radial strain was positively correlated with bioavailable testosterone level (r=0.38, P<.05). The absolute value of circumferential strain was positively correlated with follicle-stimulating hormone (r=0.65, P<.0001). These data support that the existence of sex dimorphism concerning left ventricular systolic cardiac function is significantly associated with testosterone levels.

Efficacy of Tribulus Terrestris for the treatment of premenopausal women with hypoactive sexual desire disorder: a randomized double-blinded, placebo-controlled trial

Although hypoactive sexual desire disorder (HSDD) is the most common sexual complaint, there is no consensus for the ideal treatment. Our study aimed to evaluate the efficacy of treating premenopausal women with HSDD with Tribulus terrestris and its effect on the serum levels of testosterone. We performed a prospective, randomized, double-blind, placebo-controlled trial, with 40 premenopausal women reporting diminished libido, receiving T. terrestris or placebo. The questionnaires FSFI and the QS-F were used to evaluate sexual dysfunction before and after treatment. Patients treated with T. terrestris experienced improvement in total score of FSFI (p < .001) and domains “desire” (p < .001), “sexual arousal” (p = .005), “lubrication” (p = .001), “orgasm” (p <.001), “pain” (p = .030) and “satisfaction” (p = .001). Treatment with placebo did not improve the scores for the “lubrication” and “pain”. QS-F scores showed that patients using T. terrestris had improvements in “desire” (p = .012), “sexual arousal/lubrication” (p = .002), “pain” (p = .031), “orgasm” (p = .004) and “satisfaction” (p = .001). Women treated with placebo did not score improvements. Women receiving T. terrestris had increased levels of free (p = .046) and bioavailable (p < .048) testosterone. T. terrestris might be a safe alternative for the treatment of premenopausal women with HSDD as it was effective in reducing the symptoms, probably due to an increase in the serum levels of free and bioavailable testosterone.

Vigorous Physical Activity is Associated with Regular Aerobic Exercise-Induced Increased Serum Testosterone Levels in Overweight/Obese Men

Testosterone is a male sex hormone and low circulating testosterone levels are associated with various health disorders in men. Obesity results in reduced circulating testosterone levels in men. Previously, we demonstrated that lifestyle modifications (combination of aerobic exercise and dietary modification) increase circulating testosterone levels in overweight/obese men. However, the effect of regular aerobic exercise on serum testosterone levels remains unclear. The purpose of this study was to investigate the effect of a 12-week aerobic exercise intervention on circulating testosterone levels in normal-weight and overweight/obese men. Sixteen normal-weight men and twenty-eight overweight/obese men completed a 12-week aerobic exercise intervention. Before and after the intervention, we measured serum total testosterone, free testosterone, and bioavailable testosterone levels, and categorized the physical activity levels (light, moderate, or vigorous) in all participants. At baseline, serum total testosterone, free testosterone, and bioavailable testosterone levels were significantly lower in overweight/obese men than in normal-weight men (all p<0.01). After the 12-week aerobic exercise intervention, serum total testosterone, free testosterone, and bioavailable testosterone levels significantly increased in overweight/obese men (p<0.01). In addition, stepwise multivariable linear regression analysis revealed the increase in vigorous physical activity was independently associated with increased serum total testosterone levels (β=0.47, p=0.011). We demonstrated that a 12-week aerobic exercise intervention increased serum total testosterone, free testosterone, and bioavailable testosterone levels in overweight/obese men. We suggest that an increase in vigorous physical activity increased circulating testosterone levels in overweight/obese men.

Testosterone therapy preserves muscle strength and power in aging men with type 2 diabetes-a randomized controlled trial.

The purpose of the study was to evaluate whether testosterone replacement therapy improves muscle mechanical and physical function in addition to increasing lean leg mass and total lean body mass in aging men with type 2 diabetes and lowered bio-available testosterone (BioT) levels. Thirty-nine men aged 50-70years with type 2 diabetes and BioT levels <7.3nmol/L were included from an academic tertiary-care medical center. Patients were randomized to testosterone gel (testosterone replacement therapy, n=20) or placebo (n=19) for 24weeks, applying a double-blinded design. Muscle mechanical function was assessed by Nottingham Leg Rig (leg extension power) and isokinetic dynamometry (knee extensor maximal isometric contraction, rate of force development (RFD100), maximal dynamic contraction (Dyn180)). Physical function was assessed by gait speed. Body composition was assessed by whole body dual-energy X-ray absorptiometry (total lean body mass, lean leg mass, total fat mass, leg fat mass). Levels of total testosterone (TotalT), BioT, free testosterone (FreeT), and sex hormone-binding globulin were measured from fasting blood samples. Coefficients (b) represent the placebo-controlled mean effect of intervention. Maximal isometric contraction (b=18.4 Nm, p=0.039), RFD100 (b=195.0Nm/s, p=0.017) and Dyn180 (b=10.2 Nm, p=0.019) increased during testosterone replacement therapy compared with placebo. No changes were observed in leg power or gait speed. Total lean body mass (b=1.9kg, p=0.001) and lean leg mass (b=0.5kg, p<0.001) increased, while total fat mass (b=-1.3kg, p=0.009) and leg fat mass (b=-0.7kg, p=0.025) decreased during testosterone replacement therapy compared with placebo. Total T (b=14.5nmol/L, p=0.056), BioT (b=7.6nmol/L, p=0.046), and FreeT (b=0.32nmol/L, p=0.046) increased during testosterone replacement therapy compared with placebo, while sex hormone-binding globulin (n=-2nmol/L, p=0.030) decreased. Knee extensor muscle mechanical function was preserved, and body composition improved substantially during testosterone replacement therapy for 24weeks compared with placebo, whereas physical function (gait speed) was unchanged in aging men with type 2 diabetes and lowered BioT levels.

Low free and bioavailable testosterone levels may predict pathologically-proven high-risk prostate cancer: a prospective, clinical trial.

To determine the predictive value of free and bioavailable testosterone levels on the detection of high-grade prostate cancer proven by histopathological examination of transrectal prostate biopsy specimens. A total of 405 patients who underwent transrectal prostate biopsy due to high prostatic specific antigen (PSA) (>2.5 ng/mL) and/or abnormal findings at digital rectal examination were included in this study. Blood free and bioavailable testosterone levels were calculated by the formula recommended by International Society for the Study of the Aging Male (ISSAM). The patients were stratified according to the D'Amico classification based on PSA levels and histological outcomes of prostate biopsies as benign, low, intermediate and high-risk prostate cancer. Patients were also divided into five groups according to the percentage of cancerous cores. Prostate cancer was detected in 160 of 405 (39.5%) patients. Total, free and bioavailable testosterone levels did not differ significantly between the patients with benign or malign histology. However, mean free (6.2 vs. 5.2 ng/dL, p=0.02) and bioavailable (151 vs. 125 ng/dL, p=0.001) testosterone levels were found to be significantly different in men with low-intermediate and high-risk prostate cancer. Moreover, a significant correlation was found between free, and bioavailable testosterone levels and percentage of cores with cancer (p=0.002 for free and p=0.016 for bioavailable testosterone, respectively). This prospective clinical study demonstrates that reduced levels of calculated blood free and bioavailable testosterone levels are associated with an increased risk of high-grade prostate cancer. Based on these findings blood free and bioavailable testosterone levels may be be thought to be an adjunctive factor in the prediction of high-risk prostate cancer.

Sex hormones and the risk of atrial fibrillation: The Multi-Ethnic Study of Atherosclerosis (MESA).

Atrial fibrillation is more prevalent in men than women. Due to these sex differences in atrial fibrillation susceptibility, we examined whether sex hormones have differing associations with atrial fibrillation risk in men and women. This analysis included 4883 (mean age = 63 ± 10 years; 39% women; 64% non-white) participants from the Multi-Ethnic Study of Atherosclerosis. Sex hormones (total testosterone, bioavailable testosterone, estradiol, and sex hormone binding globulin) were measured at baseline (2000-2002) for all male and all postmenopausal female participants. Atrial fibrillation was ascertained by hospital discharge records, Medicare claims data, and study electrocardiograms through December 31, 2012. Over a median follow-up of 10.9 years, a total of 613 (13%) atrial fibrillation cases were detected. A higher incidence rate of atrial fibrillation was observed for males (n = 385, age-standardized incidence rate per 1000 person-years = 12.3, 95%CI = 11.1, 13.6) than females (n = 228, age-standardized incidence rate per 1000 person-years = 9.0, 95%CI = 7.9, 10.3). In men, higher bioavailable testosterone levels were associated with increased atrial fibrillation risk (HR = 1.32, 95%CI = 1.01, 1.74; p = 0.044; comparing 3rd to 1st tertile), while an association in the opposite direction was observed for women (HR = 0.81, 95%CI = 0.58, 1.13; p = 0.22; comparing 3rd to 1st tertile). Other hormones were not associated with atrial fibrillation in men or women. Higher levels of endogenous bioavailable testosterone contribute to atrial fibrillation development in men. The combination of endogenous bioavailable testosterone and other risk factors potentially are important for atrial fibrillation development in men.

MR spectroscopy of hepatic fat and adiponectin and leptin levels during testosterone therapy in type 2 diabetes: a randomized, double-blinded, placebo-controlled trial

Men with type 2 diabetes mellitus (T2D) often have lowered testosterone levels and an increased risk of cardiovascular disease (CVD). Ectopic fat increases the risk of CVD, whereas subcutaneous gluteofemoral fat protects against CVD and has a beneficial adipokine-secreting profile. Testosterone replacement therapy (TRT) may reduce the content of ectopic fat and improve the adipokine profile in men with T2D. A randomized, double-blinded, placebo-controlled study in 39 men aged 50-70 years with T2D and bioavailable testosterone levels <7.3 nmol/L. Patients were randomized to TRT (n = 20) or placebo gel (n = 19) for 24 weeks. Thigh subcutaneous fat area (TFA, %fat of total thigh volume), subcutaneous abdominal adipose tissue (SAT, % fat of total abdominal volume) and visceral adipose tissue (VAT, % fat of total abdominal volume) were measured by magnetic resonance (MR) imaging. Hepatic fat content was estimated by single-voxel MR spectroscopy. Adiponectin and leptin levels were measured by in-house immunofluorometric assay. Coefficients (b) represent the placebo-controlled mean effect of intervention. TFA (b = -3.3 percentage points (pp), P = 0.009), SAT (b = -3.0 pp, P = 0.006), levels of adiponectin (b = -0.4 mg/L, P = 0.045), leptin (b = -4.3 µg/mL, P < 0.001), leptin:adiponectin ratio (b = -0.53, P = 0.001) and HDL cholesterol (b = -0.11 mmol/L, P = 0.009) decreased during TRT compared with placebo. Hepatic fat content and VAT were unchanged. The effects of TRT on cardiovascular risk markers were ambiguous. We observed potentially harmful changes in cardiovascular risk parameters, markedly reduced subcutaneous fat and unchanged ectopic fat during TRT and a reduction in adiponectin levels. On the other hand, the decrease in leptin and leptin:adiponectin ratio assessments could reflect an amelioration of the cardiovascular risk profile linked to hyperleptinaemia in ageing men with T2D.

Testosterone and Its Bioactive Components Are Associated with Libido and the Metabolic Syndrome in Men

Background: Some evidence has shown that the prevalence of hypoactive sexual desire and erectile dysfunction (ED) is associated with testosterone levels whilst higher levels of testosterone have been reported to increase the frequency of intercourse. Available evidence points towards an etiologic role for hypogonadism in the causation of diabetes, metabolic syndrome (Mets) and sexual dysfunction (SD) even though the exact pathophysiological linkage is yet to be fully elucidated. This study therefore sought to evaluate the impact of testosterone as well as its bioactive components on both the MetS and SD. Method: Diabetic men engaged in a stable heterosexual relationship for at least 2 years were recruited for this study. Participants were at least 18 years and provided an informed and signed consent to partake in this study. Fasting blood samples were taken from the participants for biochemical and hormonal assay. The participants were then evaluated using the Golombok Rust Inventory of Sexual Satisfaction for males (GRISS-M). Metabolic syndrome was assessed using the NCEP-ATP III, IDF and WHO criteria. All data analyses were performed using the SPSS software, version 11.0 systat, Inc. Germany and GraphPad Prism, version 5.0, San Diego California, USA. Results: The mean total, free and bioavailable testosterone as well as SHBG recorded among the participants was 7.10 ± 1.23 ng/ml, 0.10 ± 0.01 ng/ml, 7.01 ± 1.41 ng/ml and 4.33 ± 1.12 nmol/l respectively. Subjects with the MetS showed significantly lower SHBG levels in comparison with subjects without the MetS. Participants with raised triglyceride levels showed significantly lower levels of total, free and bioavailable testosterone when compared to participant without raised triglycerides. Participants with problems of avoidance and infrequency of sexual activity showed significantly lower levels of total, free and bioavailable testosterone when compared to participants without avoidance or infrequency problems. The +SD/+MetS group recorded the lowest SHBG levels. Conclusion: Testosterone and its bioactive components are associated with male libido as well as the metabolic syndrome. Low levels of free and bioavailable testosterone are true determinants of the MetS in men.

A higher score on the Aging Males' Symptoms scale is associated with insulin resistance in middle-aged men.

An age-associated androgen decrease and its pathological conditions are defined as late-onset hypogonadism (LOH). Among the various symptoms associated with LOH, a visceral fat increase is strongly associated with relatively low levels of testosterone. However, few studies have investigated the relationship between the Aging Males' Symptoms (AMS) scores and metabolic abnormalities. Thus, we aimed to clarify this relationship by investigating the relationship between AMS scores and various markers in blood. During routine health examinations in 241 middle-aged males (52.7±7.5 years of age, mean±SD), 150 males (62.2%) displayed higher AMS values than normal. No statistical association was observed between total AMS scores and any testosterone value. All mental, physical and sexual AMS subscales were significantly positively correlated with insulin levels and HOMA-IR. Only sexual subscale scores were significantly inversely associated with free or bioavailable testosterone level. Males with insulin resistance (HOMA-IR≥2.5) demonstrated significantly higher AMS scores than those with normal insulin sensitivity (HOMA-IR<2.5). AMS values were positively correlated with fasting blood glucose, insulin and HOMA-IR values. Interestingly, univariate and multivariate analyses revealed that HOMA-IR≥2.5 was a significant predictor for detection of moderately severe AMS values (AMS≥37), whereas AMS≥37 was not a predictor of metabolic syndrome by International Diabetes Federation (IDF) criterion. In conclusion, almost 60% of healthy male subjects displayed abnormal AMS scores. AMS values were not associated with testosterone values but rather were related to insulin resistance, particularly in subjects with moderately severe AMS values. Insulin resistance-related general unwellness might be reflected by AMS values.

Hematopoiesis Shows Closer Correlation with Calculated Free Testosterone in Men than Total Testosterone.

Serum total testosterone (tT)9 includes both free testosterone (fT) (0.5%–3% of total and believed to be the biologically active form) and sex hormone–binding globulin (SHBG)- and albumin-bound forms (1). Guidelines for diagnosing and treating male hypogonadism that emphasize measurement of tT (2) may not address the major variations in SHBG and consequent testosterone bioavailability (testosterone bioavailability [BT] either calculated or assayed directly) that are associated with age, obesity, anticonvulsant therapy, and thyroid and liver disease. For these reasons, recent Endocrine Society of Australia guidelines (3) acknowledge the value of measuring SHBG as well as BT, but nevertheless state that, “There is no evidence that free or bioavailable testosterone levels, which are usually not directly measured but calculated…are a better measure of androgen status than total testosterone level. Moreover, reference intervals for these [BT levels] are even less well defined than those for measured testosterone concentrations. Therefore, they [BT levels] are not recommended for clinical decision-making.” Although commercially available direct fT assays are not always robust, calculated fT (c-fT) values from a mass-action …