The association of testosterone with sarcopenia and frailty in chronic liver disease.

BACKGROUND: Testosterone is an important anabolic hormone responsible for maintaining body composition and muscle mass and circulates mostly albumin-bound, or sex hormone binding globulin (SHBG)-bound or free in the plasma. Of these fractions, the latter is bioactive and exerts the androgenic effects on male population. Liver cirrhosis, the advanced stage of any chronic liver disease characterized by permanent distortions to the hepatic architecture, disrupts the hypothalamic-pituitary-gonadal axis, leading to diminished levels of free testosterone and hypogonadism. METHODS: We retrieved the PubMed database to provide a synopsis of testosterone's physiology and action and summarize the effect of sarcopenia in pre-cirrhotic and cirrhotic patients. Moreover, we scoped to provide insight into the relationship of testosterone levels with sarcopenia, frailty and survival in cirrhotic and non-cirrhotic population as well as to discuss the efficacy of exogenous testosterone supplementation on the anthropometric parameters and survival of those patients. RESULTS: Low testosterone levels have been associated with sarcopenia, reduced body lean mass, decreased bone mineral density and frailty, thus leading to increased morbidity and mortality especially among cirrhotic patients. Furthermore, exogenous testosterone administration significantly ameliorated body composition on patients with chronic hepatic disease, without significant adverse effects. However, the current literature does not suggest any significant effect on survival of those patients. Moreover, the long-term safety of testosterone use remains an open question. CONCLUSION: Low serum testosterone is strongly correlated with sarcopenia, frailty, higher rate of hepatic decompensation and mortality. Nonetheless, exogenous supplementation of testosterone did not ameliorate the liver-related outcomes and complications.

Men treated with BEACOPP for Hodgkin lymphoma may be at increased risk of testosterone deficiency.

In the current study, we report the prevalence of male testosterone deficiency in a cohort of 60 male long-term survivors of malignant lymphoma with normal total testosterone but in the lower part of the reference level. Testosterone deficiency was defined as subnormal concentrations of total testosterone or subnormal concentrations of calculated free testosterone. The aim was to clarify whether total testosterone was sufficient for identification of testosterone deficiency in male survivors of malignant lymphoma. Hormonal analyses taken at follow-up were compared with samples taken at diagnosis for a subgroup of 20 survivors, for evaluation of changes in hormones over time. Another group of 83 similar survivors of malignant lymphoma with testosterone in the high end of reference levels were also used for comparison, to identify groups of increased risk of testosterone deficiency. A total group of 143 survivors were therefore included in the study. Our findings indicate that for screening purposes an initial total testosterone is sufficient in some survivors because sexual hormone binding globulin concentration was found stable over time. However, 15% were found with subnormal calculated free testosterone. Survivors intensely treated for Hodgkin lymphoma and older survivors were identified as high-risk groups for testosterone deficiency necessitating endocrinological attention during follow-up. Some evidence of pituitary downregulation was also found, because of uncompensated decreases in testosterone concentration over time. In conclusion, longitudinal measurements of total testosterone alone do not seem adequate for the screening of testosterone deficiency for all long-term lymphoma survivors.

Effects of depot medroxyprogesterone acetate, the copper IUD and the levonorgestrel implant on testosterone, sex hormone binding globulin and free testosterone levels: ancillary study of the ECHO randomized clinical trial.

BACKGROUND: Robust information on relative effects of hormonal contraceptives on endogenous androgens is important for understanding beneficial and adverse effects, method choice and development of new methods. METHODS: In this ancillary study at the East London, South Africa site of the ECHO multicentre randomized trial, we compared effects of three contraceptive methods on serum androgen levels among contraceptive users aged 18 to 35 years. Participants were allocated by centrally-managed randomization to open label depot medroxyprogesterone acetate (DMPA-IM), copper intrauterine device (IUD) or levonorgestrel implant. The primary outcome was free testosterone at 6 months. RESULTS: We analysed stored baseline and 6-month serum samples in 398/615 participants (DMPA-IM 131/205, IUD 135/205 and implant 132/205). Median testosterone levels at baseline were DMPA-IM 0.82, IUD 0.9 and implant 0.87 nmol/L; at 6 months, DMPA 0.68 (lower than IUD, mean percentage difference 28.35, (p <  0.001), IUD 0.86 (unchanged) and implant 0.66, lower than IUD, mean percentage difference - 22.98, p <  0.001). Median SHBG levels at baseline were DMPA 52.4, IUD 50.5 and implant 55.75 nmol/L; at 6 months, DMPA 40.65, lower than IUD (mean percentage difference 21.19, p = 0.005), IUD 49.1 (unchanged), and implant 23.35 nmol/L, lower than IUD (mean percentage difference - 50.04, p <  0.001 and than DMPA (mean percentage difference - 39.45, p <  0.001). Free testosterone levels at baseline were DMPA 10, IUD 12 and implant 11 pmol/L; at 6 months, DMPA 11, less than IUD (mean percentage difference 13.53, p = 0.047), IUD 12 and implant 14, higher than IUD (mean percentage difference 14.15, p = 0.038) and than DMPA, (mean percentage difference 29.60, p < 0.001). CONCLUSIONS: This is the first randomized trial to show lower SHBG and higher free testosterone with the levonorgestrel implant than with DMPA, and contrasts with reports of increased SHBG with combined oral ethinyl estradiol/levonorgestrel use, and reduced androgens (and impaired sexual function) reported with the etonorgestrel implant. The higher free testosterone with the LNG implant might improve sexual function, mood and bone health as well as increasing side-effects such as acne and hirsutism, and is consistent with the greater sexual activity (with respect to multiple sex partners, new sex partner and unprotected sex) with the implant compared with DMPA documented in the ECHO study. ECHO TRIAL REGISTRATION: ClinicalTrials.gov , number NCT02550067 15/09/2015. Contraception, or family planning, is central to the role of women in societies. It is most important to have accurate information on the relative side-effects of various contraceptive options in order to empower women to make informed choices regarding their preferred method. Hormonal contraceptives contain various forms of the female sex hormones, estrogens and/or progestogens. These hormones have direct effects on the users, as well as modifying the levels of the users' own circulating sex hormones, both the 'female' and the 'male' sex hormones (androgens). In this study, consenting participants requesting contraception, were allocated randomly to receive either depot medroxyprogesterone acetate (DMPA-IM) a 3-monthly progestogen injection, the copper intrauterine device (IUD), a non-hormonal contraceptive inserted within the womb, or the levonorgestrel implant, a device placed under the skin which releases a progestogen for 5 years. We measured the participants' androgen levels after 6 months, and found for the first time that the active form of testosterone (free testosterone) was 29% higher with the implant than with DMPA-IM. The level with the IUD was intermediate, and significantly different from the other two methods. This finding is relevant to the effects experienced by users of these methods, because free testosterone has effects on sexual function, bone health and mood, as well as on conditions such as acne and hair distribution patterns.

Simultaneous quantification of total and free testosterone in human serum by LC-MS/MS.

Testosterone (TTe) and free testosterone (FTe) are clinically important indicators for the diagnosis of androgen disorders, so accurate quantitative determination of them in serum is clinically of paramount significance. Currently, there is no available method suitable for routine and simultaneous measurement of TTe and FTe. Here, we developed a new UPLC-MS/MS method to quantify serum TTe and FTe simultaneously and accurately. Rapid equilibrium dialysis was used to obtain FTe in serum followed by derivatization with hydroxylamine hydrochloride. With these strategies, TTe and FTe could be measured in single injection. After optimizing the extraction and derivatization conditions, the performance of LC-MS/MS was evaluated and applied to quantify the levels of TTe and FTe in clinical samples from 42 patients. The assays were linear for TTe within the range of 0.2-30 ng/mL and for FTe within the range of 1.5-1000 pg/mL. This improved method provided a limit of quantification for TTe of 0.2 ng/mL and for FTe of 1.5 pg/mL. The intra- and inter-run CVs were less than 4.3% and 3.6% for TTe and less than 8.2% and 6.7% for FTe, respectively. The intra- and inter-run accuracies for both TTe and FTe were in the range of 96.1-108.1%. Interference, carryover effect, and matrix effect were in acceptable range. In conclusion, our new LC-MS/MS method is simple to perform and can serve as a reliable method for simultaneous determination of TTe and FTe in clinical practice, providing important information for diagnosis, treatment, and monitoring of androgen-related diseases.

Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology.

According to the free hormone hypothesis, biological activity of a certain hormone is best reflected by free rather than total hormone concentrations. A crucial element in this theory is the presence of binding proteins, which function as gatekeepers for steroid action. For testosterone, tissue exposure is governed by a delicate equilibrium between free and total testosterone which is determined through interaction with the binding proteins sex hormone-binding globulin and albumin. Ageing, genetics and various pathological conditions influence this equilibrium, hereby possibly modulating hormonal exposure to the target tissues. Despite ongoing controversy on the subject, strong evidence from recent in vitro, in vivo and human experiments emphasizes the relevance of free testosterone. Currently, however, clinical possibilities for free hormone diagnostics are limited. Direct immunoassays are inaccurate, while gold standard liquid chromatography with tandem mass spectrometry (LC-MS/MS) coupled equilibrium dialysis is not available for clinical routine. Calculation models for free testosterone, despite intrinsic limitations, provide a suitable alternative, of which the Vermeulen calculator is currently the preferred method. Calculated free testosterone is indeed associated with bone health, frailty and other clinical endpoints. Moreover, the added value of free testosterone in the clinical diagnosis of male hypogonadism is clearly evident. In suspected hypogonadal men in whom borderline low total testosterone and/or altered sex hormone-binding globulin levels are detected, the determination of free testosterone avoids under- and overdiagnosis, facilitating adequate prescription of hormonal replacement therapy. As such, free testosterone should be integrated as a standard biochemical parameter, on top of total testosterone, in the diagnostic workflow of male hypogonadism.

Diagnostic value of anti-Müllerian hormone combined with androgen-levels in Chinese patients with polycystic ovary syndrome.

OBJECTIVE: To establish a cutoff level of AMH which could help for the diagnosis of PCOS, to investigate the predictive value of AMH combined with androgens in Chinese women to diagnose PCOS. MATERIALS AND METHODS: This is a prospective case control study, 550 women recruited (aged 20-40 years), in which 450 PCOS women recruited according to the Rotterdam criteria and 100 non-PCOS women in the control group were from the women for the pregnancy preparation examination. AMH were measured by the Elecsys AMH Plus immunoassay. Androgens and other sex hormone were measured. The validity of AMH toward the diagnosis of PCOS, or AMH combined with total testosterone, free testosterone, bioavailable testosterone and androstenedione was estimated by receiver operating characteristic (ROC)curves, and correlations between paired variables was estimated by Spearman's rank correlation coefficient. RESULTS: The cutoff value of AMH in Chinese reproductive-age women with PCOS is 4.64 ng/mL, AUC under the curve is 0.938, with 81.6% sensitivity, and 92.0% specificity. Total testosterone, free testosterone, bioactive testosterone, and androstenedione are significantly higher in women with PCOS of reproductive age than in controls. The combination of AMH and free testosterone resulted in a higher AUC of 94.8%, with higher sensitivity (86.1%) and excellent specificity (90.3%) for the prediction of PCOS. CONCLUSION: The Elecsys AMH Plus immunoassay, with a cutoff of 4.64 ng/mL, is a robust method for identifying PCOM to aid in PCOS diagnosis. The combination of AMH and free testosterone resulted in a higher AUC of 94.8% for the diagnose of PCOS.

Diagnosis of hypogonadism in ageing men.

To make the diagnosis of hypogonadism in an ageing man, in absence of rare organic cause often referred to as functional or late onset hypogonadism (LOH), he should present with a clinical syndrome suggestive of androgen deficiency and have consistently low serum testosterone (T) levels. This does not differ from the diagnosis of any other form of hypogonadism. Particular to LOH diagnostic are uncertainties surrounding this entity: signs and symptoms of androgen deficiency (including sexual symptoms) are nonspecific in older men; clinical significance of only moderately low T levels is uncertain; comorbidity plays a substantial role with potential for reversibility; the place of T therapy in these men is debatable. This context demands for a pragmatic, but appropriately conservative approach to diagnosis. Evaluation should be stepwise with clinical evaluation, if suggestive for androgen deficiency, followed by measurement of a fasting morning serum T, if unequivocally low to be confirmed in a separate morning sample by a second low T or, if initial T borderline low or in presence of factors known to affect SHBG, by a low calculated free T level. All other (free) T results make hypogonadism an unlikely cause of the patient's symptoms. In the absence of consensus cut-off levels for total and free T in the published clinical guidelines for diagnosis of hypogonadism, it seems appropriate in the context of LOH to use stringent criteria indicating a convincingly low serum T. The approach to the diagnosis of LOH is not fundamentally different from that of other forms of hypogonadism but should put extra weight on prioritizing the shunning of overdiagnosis above the risk of underdiagnosis.

Usefulness of routine assessment of free testosterone for the diagnosis of functional male hypogonadism.

OBJECTIVE: To investigate whether routine assessment of free testosterone improves the diagnostic accuracy of functional hypogonadism. METHODS: Total and free testosterone (calculated on SHBG levels) were determined in 188 patients with sexual symptoms and 184 with infertility. RESULTS: Hypogonadism (calculated free testosterone <63 pg/ml) was found in 47/188 (25.0%) patients with sexual symptoms and in 21/184 (11.4%) with infertility. Total testosterone determination misdiagnosed hypogonadism in 8.4% (12/143) of men with sexual symptoms and in 2% (3/152) with infertility. In subjects with borderline total testosterone, only 24.7% (19/77) had hypogonadism confirmed by free testosterone levels. Free testosterone levels significantly correlated with age, haematocrit, gonadotropins, gynecomastia, BMI, and number of co-morbidities, whereas total testosterone associated only with the latter two. Furthermore, age, haematocrit, BMI, and the presence of erectile dysfunction and of low libido were significantly different between men with normal and low free testosterone, whereas only BMI and low libido were significantly different between patients with normal and low total testosterone. CONCLUSION: Routine assessment of free testosterone allows a more accurate diagnosis of functional hypogonadism, especially in men with sexual symptoms. Free testosterone levels associate with clinical and biochemical parameters of androgen deficiency better than total testosterone levels.

Free testosterone is related to aspects of cognitive function in women with and without polycystic ovary syndrome.

Evidence suggests impairment in aspects of cognitive function in women with polycystic ovary syndrome (PCOS). Direct effects of raised testosterone levels associated with PCOS are a potential mechanism. We aimed to explore the relationship between testosterone levels and cognitive functioning in women. Women with a range of testosterone levels, including women with PCOS, were recruited. Depressive and anxiety symptoms were measured by self-report. Participants underwent a comprehensive battery of cognitive tests assessing psychomotor speed, visuospatial learning and memory, verbal learning and memory, and executive function. Free testosterone serum levels were assessed. All measures were completed at the same time point. Correlation analysis (Spearman's Rho) was used to explore associations between free testosterone and cognitive test variables. Eighty-one women were recruited, with 40 meeting diagnostic criteria for PCOS. Free testosterone was normally distributed, with significant overlap between women with PCOS and controls. Mean depressive and anxiety symptoms were in the mild range. Higher free testosterone levels were significantly correlated with poorer performance on measures assessing psychomotor speed and visuospatial learning. These significant correlations remained after adjusting for confounders (premorbid verbal IQ, depressive, and anxiety symptoms). Higher free testosterone levels in women were associated with poorer cognitive function, specifically psychomotor speed and visuospatial learning. Women with PCOS and raised free testosterone levels may experience impairment in these aspects of cognitive function which are not accounted for by mood or anxiety symptoms.

Late-Onset Hypogonadism in a Male Patient with Long COVID Diagnosed by Exclusion of ME/CFS.

After the acute phase of COVID-19, some patients have been reported to have persistent symptoms including general fatigue. We have established a COVID-19 aftercare clinic (CAC) to provide care for an increasing number of these patients. Here, we report the case of a 36-year-old man who developed post-COVID fatigue after acute infection with SARS-CoV-2. In the acute phase of COVID-19, the patient's fever resolved within four days; however, general fatigue persisted for three months, and he visited our CAC 99 days after the initial infection. Examination revealed a high Aging Male's Symptoms (AMS) score of 44 and low free testosterone (FT) level of 5.5 pg/mL, which meet the Japanese criteria of late-onset hypogonadism (LOH) syndrome. Imaging studies revealed an atrophic pituitary in addition to fatty liver and low bone mineral density. Anterior pituitary function tests showed a low follicle-stimulating hormonelevel and delayed reaction of luteinizing hormone (LH) after gonadotropin-releasing hormone (GnRH) stimulation, indicating the possibility of hypothalamic hypogonadism in addition to primary hypogonadism seen in patients with post-COVID-19 conditions. After the initiation of Japanese traditional medicine (Kampo medicine: hochuekkito followed by juzentaihoto), the patient's symptoms as well as his AMS score and serum FT level were noticeably improved. Furthermore, follow-up tests of GnRH stimulation revealed improvements in LH responsiveness. Although many patients have been reported to meet the criteria of ME/CFS such as our case, we emphasize the possibility of other underlying pathologies including LOH syndrome. In conclusion, LOH syndrome should be considered a cause of general fatigue in patients with post-COVID-19 conditions and herbal treatment might be effective for long COVID symptoms due to LOH (264 words).

Molecular interactions between sex hormone-binding globulin and nonsteroidal ligands that enhance androgen activity.

Sex hormone-binding globulin (SHBG) determines the equilibrium between free and protein-bound androgens and estrogens in the blood and regulates their access to target tissues. Using crystallographic approaches and radiolabeled competitive binding-capacity assays, we report here how two nonsteroidal compounds bind to human SHBG, and how they influence androgen activity in cell culture. We found that one of these compounds, (-)3,4-divanillyltetrahydrofuran (DVT), present in stinging nettle root extracts and used as a nutraceutical, binds SHBG with relatively low affinity. By contrast, a synthetic compound, 3-(1H-imidazol-1-ylmethyl)-2phenyl-1H-indole (IPI), bound SHBG with an affinity similar to that of testosterone and estradiol. Crystal structures of SHBG in complex with DVT or IPI at 1.71-1.80 Šresolutions revealed their unique orientations in the SHBG ligand-binding pocket and suggested opportunities for the design of other nonsteroidal ligands of SHBG. As observed for estradiol but not testosterone, IPI binding to SHBG was reduced by ∼20-fold in the presence of zinc, whereas DVT binding was almost completely lost. Estradiol-dependent fibulin-2 interactions with SHBG similarly occurred for IPI-bound SHBG, but not with DVT-bound SHBG. Both DVT and IPI increased the activity of testosterone in a cell culture androgen reporter system by competitively displacing testosterone from SHBG. These findings indicate how nonsteroidal ligands of SHBG maybe designed to modulate the bioavailability of sex steroids.

Sociodemographic, lifestyle and medical influences on serum testosterone and sex hormone-binding globulin in men from UK Biobank.

OBJECTIVE: Serum testosterone concentrations are affected by factors unrelated to hypothalamo-pituitary-testicular axis pathology. We evaluated the impact of sociodemographic, lifestyle and medical factors, on serum testosterone and sex hormone-binding globulin (SHBG) in men aged 40-69 years. DESIGN: Cross-sectional analysis of 208,677 community-dwelling men from the UK Biobank. MEASUREMENTS: We analysed associations of different factors with serum testosterone and SHBG (immunoassays) and calculated free testosterone (cFT), using smoothed centile plots, linear mixed models and effect size estimates. RESULTS: Median (interquartile range) for serum testosterone was 11.6 (9.4-14.1) nmol/L, SHBG 36.9 (27.9-48.1) nmol/L and cFT 213 (178-255) pmol/L. Age and BMI were inversely associated with testosterone and cFT, while SHBG was associated with age and inversely with BMI (all P < .001). Living with a partner, (South) Asian ethnicity, never or previous smoker and some medical conditions were associated with lower testosterone. Poultry or fish eater, and higher physical activity were associated with higher testosterone (all P < .001). Testosterone was lowered by ~0.5 nmol/L across ages, ~1.5 nmol/L for BMI 30 vs 25 kg/m2 , ~2 nmol/L for (South) Asian ethnicity, living with partner, college/university qualifications, low red meat eater, insufficient physical activity and 0.3-1.0 nmol/L with cardiovascular disease or diabetes. Different combinations of these factors varied serum testosterone by ~4 nmol/L, SHBG by ~30 nmol/L and cFT by ~60 pmol/L. CONCLUSIONS: The identified modifiable risk factors support lifestyle-based interventions in men with low testosterone concentrations. Considering sociodemographic, lifestyle and medical factors facilitates more personalized interpretation of testosterone testing results with respect to existing reference ranges.

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.

The importance of SHBG and calculated free testosterone for the diagnosis of symptomatic hypogonadism in HIV-infected men: a single-centre real-life experience.

PURPOSE: The prevalence of low testosterone and symptoms of hypogonadism in HIV-infected men is still debated. We aimed to estimate the prevalence and type of hypogonadism in HIV-infected males complaining about sexual symptoms, and to evaluate the role of calculated free testosterone (cFT) vs total testosterone (TT) for diagnosis. Furthermore, we evaluated relationship between sex hormone-binding globulin (SHBG), gonadal status and clinical and virologic parameters. METHODS: We retrospectively evaluated 169 HIV-infected men with sexual symptoms, with TT available. Among them, we selected 94 patients with TT, SHBG, cFT, and luteinizing hormone (LH) available, and classified hypogonadism into overt (low TT and/or low cFT) and compensated (high LH, normal TT and cFT). Comparison was performed by non-parametric Kruskal-Wallis test and Spearman's correlation was calculated to verify the possible associations. RESULTS: Overt and compensated hypogonadism were found in 20.2% and 13.8% of patients, respectively. With reliance on TT alone, only 10.6% of patients would have met diagnosis. SHBG values were elevated in one third of patients, and higher in men with compensated hypogonadism. Significant positive correlation was found between SHBG and HIV infection duration, TT and LH. CONCLUSION: Only a complete hormonal profile can properly diagnose and classify hypogonadism in HIV-infected men complaining about sexual symptoms. TT alone reliance may lead to half of diagnoses missing, while lack of gonadotropin prevents the identification of compensated hypogonadism. This largely comes from high SHBG, which seems to play a central role in the pathogenesis of hypogonadism in this population.

Association of hypogonadism symptoms and serum hormones in aging males.

The association between hypogonadism symptoms and the levels of serum hormones are still in debate. To investigate the relationship between hypogonadism symptoms and serum hormones in middle-aged and elderly Chinese men, this community-based cross-sectional study was conducted based on a total of 965 ageing men. The ageing males' symptom (AMS) scale, International Index of Erectile Function-5 (IIEF-5), International Prostate Symptom Score (IPSS) questionnaires and related variables were assessed. Blood tests for total testosterone (TT), sex hormone-binding globulin (SHBG) and luteinising hormone (LH) were performed. Serum level of free testosterone (FT) and bioavailable testosterone (Bio-T) was calculated. The mean age was 56.34 ± 8.85 years. Total AMS score was significantly associated with all five serum hormones (LH: p < 0.001; SHBG: p < 0.001; TT: p =.043; FT: p = 0.007; Bio-T: p < 0.001). We identified sexual and somatic symptoms were obviously related to five serum hormones, while psychological symptoms seemed to have no association with serum hormones. After adjusting for age and BMI, multiple linear regression analysis indicated that LH had positive correlations with total AMS score, somatic and sexual symptom score (p < 0.05). In conclusion, LH and SHBG had the strongest correlation hypogonadism and might be used as early predictors for symptomatic hypogonadism in the near future.

Free testosterone levels and their association with body composition in women with chronic kidney disease.

Data concerning the influence of sex hormones on body composition in women with chronic kidney disease (CKD) is limited. AIM: The aim of our study was to define free testosterone levels and their association with body composition, biochemical markers of nutrition in females with CKD. MATERIALS AND METHODS: 47 women were included into the study. 13 females treated with hemodialysis formed the hemodialysis group (HD), 24 females with CKD stage IV/V (eGFR < 30 ml/min/1,73 m2) formed the predialysis group (PreD), and 10 females without kidney disease formed the control group (C). Lean tissue mass (LTM) and fat mass (Fat) were measured using bioimpedance spectroscopy. Free testosterone levels were assessed using ELISA (IBL International). Statistical analysis was performed using Statistica v 13.1. RESULTS: The median free testosterone (fT) levels were 0.7, 0.6, 0.85 pg/ml respectively for HD, PreD and C group. The median fT did not differ significantly between the groups (p=0.24). The mean LTM was 28.5 ±5.6, 27.3 ±4.9, 30.6 ±4.3 kg, mean Fat mass was 22.7 ±8.5, 31.3 ±9.8, 31.6 ±8.5 kg for the HD, PreD and C groups respectively. Positive correlations were observed between fT and LTM (r=0.306, p=0.035) in the whole study group. A negative correlation was observed between fT and age (r=-0.284) but was on the border of statistical significance (p=0.052). CONCLUSIONS: In women with advanced CKD, median testosterone levels did not differ significantly from those observed in women without kidney failure. Free testosterone levels were associated with the amount of muscle mass in the whole study population.

Association between testosterone with type 2 diabetes in adult males, a meta-analysis and trial sequential analysis.

OBJECTIVE: We performed this meta-analysis to assess serum testosterone changes in adult males with Type 2 diabetes (T2DM). METHODS: PubMed, Embase, Web of Science, and Cochrane Library were searched to identify qualified studies. Pooled weighted mean differences (WMDs) with 95% confidence intervals (CIs) were utilized to test the changes of total testosterone (TT), free testosterone (FT) and sex hormone-binding globulin (SHBG) in patients with T2DM. Besides, trial sequential analysis was used to verify the pooled results. RESULTS: A total of 56 studies were enrolled in our meta-analysis. Meta-analyses of the cross-sectional studies showed that patients with T2DM has significant decreases in TT (WMD: -2.98, 95%CI: -3.48 to -2.47), FT (WMD: -32.82, 95%CI: -39.70 to -25.95) and SHBG (WMD: -2.47, 95%CI: -3.93 to -1.02). In terms of the prospective studies, our results showed decreases in TT (WMD: -2.35, 95%CI: -3.24 to -1.46), FT (WMD: -25.96, 95%CI: -83.98 to 32.05), and SHBG (WMD: -10.06, 95%CI: -13.29 to -6.84) in patients with T2DM. By trial sequential analyses, the findings in current meta-analysis were based on reliable evidence. CONCLUSION: Our results indicate that patients with T2DM have lower serum TT, FT, and SHBG levels.

Endogenous transient doping: physical exercise acutely increases testosterone levels-results from a meta-analysis.

PURPOSE: Although endogenous testosterone levels are demonstrated to be affected by both acute exercise and resistance training, the dynamic regulation of androgen production after physical activity is still a matter of debate. This meta-analysis was designed to assess whether physical exercise acutely affects testosterone levels in men. METHODS: The literature search was conducted to identify longitudinal trials evaluating the acute change of both total testosterone (TT) and free testosterone (fT) after physical activity in adult men. Sensitivity analyses were performed considering the sample collected (blood or saliva), the intensity of the physical exercise and the interval between the end of the exercise and the sample collection. RESULTS: Forty-eight studies were included in the analysis, accounting for 126 trials. A total of 569 patients were enrolled (mean age 29.7 ± 13.1 years). The physical activity increased acutely TT (standardized mean difference 0.74, 95%CI: 0.56, 0.91 nmol/L), considering both serum and saliva samples (p < 0.001). Testosterone increased after moderate (p < 0.001) and high-intensity (p < 0.001) exercises, but not after mild physical activity (p = 0.19). Moreover, the testosterone increase was evident when measured immediately at the end of the exercise and within 30 min (p < 0.001), but not after 30 min (p = 0.930). Similar significant results were obtained considering fT, while SHBG did not change after physical activity (p = 0.090). CONCLUSION: The comprehensive evaluation of the acute physical activity effect on testosterone levels identified a clear increase after exercise, irrespective of the sample collected. The main determinant of this fluctuation was the exercise intensity, with a mechanism that seems to be mostly SHBG independent. In particular, moderate/intense physical activity resulted able to increase endogenous androgenic production, albeit acutely and transitory. TRIAL REGISTRATION NUMBER: PROSPERO registration ID: 157348.

Clinical practice update on testosterone therapy for male hypogonadism: Contrasting perspectives to optimize care.

US Endocrine Society (ES) published a clinical practice guideline on testosterone therapy in men with hypogonadism, and Endocrine Society of Australia (ESA) a position statement on management of male hypogonadism. Both emphasize the importance of diagnosing men who are androgen deficient due to organic (classical or pathological) hypogonadism arising from disorders of the hypothalamus, pituitary or testes, who assuredly benefit from testosterone therapy. Both recognize that men with an intact gonadal axis may have low testosterone concentrations, for instance older men or men with obesity or other medical comorbidities. ES guidelines classify such symptomatic men as having organic (advanced age) or functional (obesity, medical comorbidities) hypogonadism, giving an option for testosterone therapy as a shared decision between clinicians and individual patients. ESA did not recommend testosterone therapy in these men. ES offers a reference range for total testosterone established in young men, while ESA cites age-standardized reference ranges. ES recommends using free testosterone as well as total testosterone to identify men with hypogonadism in conditions where sex hormone-binding globulin (SHBG) is altered, or when total testosterone is borderline. ESA recommends confirmatory biochemical testing with total testosterone, recognizing that this may be lower than expected if SHBG concentrations are low. Both emphasize the importance of identifying pre-existing prostate and cardiovascular disease prior to initiating testosterone therapy, with ES providing specific recommendations for PSA measurement, deferring testosterone therapy after major cardiovascular events and indications for pituitary imaging. These contrasting approaches highlight gaps in the evidence base where individualized patient management is required.

Free testosterone value before radical prostatectomy is related to oncologic outcomes and post-operative erectile function.

PURPOSE: To investigate whether free testosterone (FT) prior to radical prostatectomy was related to post-operative oncologic outcomes, erectile function and continence. METHODS: The data of 586 patients with available information underwent treatment in our center was retrospectively reviewed. Total testosterone (TT) was tested by chemiluminescence immunoassay, and FT value was calculated using Vermeulen's formula. Post-operative continence and erectile function were evaluated by the requirement of pad and the IIEF-5 score at 12 months. RESULTS: The median TT and FT value was 344 ng/dL (interquartile, IQR 314-374) and 6.9 ng/dL (IQR 6.4-7.3), and 106 patients (18.1%) and 152 patients (25.9%) were evaluated as having low TT and low FT based on current guidelines. Low TT and FT value were both related to older age (both p < 0.001), concomitant diabetes (p = 0.018 & 0.049), higher possibility of pre-operative erectile dysfunction (ED, both p < 0.001), higher pre-operative PSA value (both p < 0.001), higher clinical stage (both p < 0.001) and higher Gleason score in biopsy (both p < 0.001). Low FT was related to higher risk for pT3 (p = 0.020) and high Gleason score (p = 0.011) in logistic regression. The median follow-up duration was 52 moths (IQR 29-67) and FT was found to be an independent risk factor for biochemical recurrence (p = 0.005). In logistic regression TT was related to pre-operative ED (p = 0.010) and FT was related to post-operative ED (p = 0.001). CONCLUSION: Low FT value before radical prostatectomy was related to adverse pathological outcomes, biochemical recurrence and post-operative ED.