Months Of Testosterone Replacement Therapy Research Articles

Prescription Testosterone is Associated with an Increased Risk of Anterior Cruciate Ligament Injury

To characterize the relationship between testosterone replacement therapy (TRT) and anterior cruciate ligament (ACL) injuries. A retrospective cohort study using a large insurance database was conducted. Patients who were prescribed TRT for at least 3 months were matched with controls who were not prescribed TRT. Rates of ACL tears were compared between the cohorts. Multiple subgroups were created based on age (<25 years, 25-35, 36-45, 46-55, 56-65, and 65+). Multivariable logistic regressions were performed to determine the association of TRT with ACL tears while accounting for demographic variables and comorbidities. After matching, there were 160,839 patients in both the TRT cohort and control cohort. The incidence of ACL injuries was 17.8 per 10,000 person-years (95% CI: 16.4-19.2) for patients who were prescribed TRT and 4.9 per 10,000 person-years (95% CI: 4.1-5.7) for controls (p<0.001). Within 2 years of filling a testosterone prescription for at least 3 months, 572 (0.35%) patients experienced an ACL injury compared to only 157 (0.10%) controls during the same follow-up period (OR: 2.77; 95% CI: 2.26-3.42, p<0.001). When stratified by age, all groups except the <25 years of age group demonstrated significantly higher rate of ACL tears (OR 3.91-12.3, p<0.001-0.009). When separated by sex, males on TRT were 3.13 (95% CI: 2.50-3.93, p<0.001) times more likely while females on TRT were 1.94 (95% CI: 1.13-3.41, p=0.018) times more likely to experience an ACL injury compared to controls. This study found that patients prescribed at least three months of TRT had a significantly higher incidence of ACL injuries compared to controls within a two-year follow-up period. Level III, retrospective comparative study.

Modulation of circulating free testosterone fraction by testosterone, dihydrotestosterone, and estradiol during testosterone replacement therapy.

Testosterone, estradiol, and dihydrotestosterone share common ligand binding sites on sex hormone binding globulin and albumin. It is unknown whether and how changes in testosterone, dihydrotestosterone, and estradiol concentrations during testosterone replacement therapy affect free testosterone fraction. To determine the effect of changes in testosterone, dihydrotestosterone, and estradiol concentrations on free testosterone fraction during testosterone replacement therapy of men with hypogonadism. Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and dihydrotestosterone concentrations over 12 months of testosterone replacement therapy with changes in free testosterone fraction, measured using equilibrium dialysis. We used random forests to evaluate the associations of predicted mean changes in free testosterone fraction with changes in circulating concentrations of each hormone at low, mean, or high change in the other two hormones. Testosterone replacement therapy not only increased total testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations, but also the percent free testosterone, even though sex hormone binding globulin levels did not change. The predicted changes in free testosterone fraction during testosterone replacement therapy exhibited a non-linear relationship with changes in each of total testosterone, dihydrotestosterone, and estradiol concentrations. Greater increases in testosterone, dihydrotestosterone, and estradiol levels during testosterone replacement therapy were each associated with higher model-predicted percent free testosterone. Substantially smaller changes in molar concentrations of estradiol and dihydrotestosterone had a greater effect on percent free testosterone than those in testosterone. During testosterone replacement therapy of men with hypogonadism, changes in testosterone, dihydrotestosterone, and estradiol concentrations each altered percent free testosterone non-linearly. Small changes in estradiol concentrations exerted much larger effect on the free testosterone fraction than testosterone and dihydrotestosterone, suggesting complex interactions of the three hormones with the binding proteins. Assessment of changes in free testosterone during testosterone replacement therapy should include consideration of changes in all three hormones.

Testosterone Replacement Therapy in Klinefelter Syndrome-Follow-up Study Associating Hemostasis and RNA Expression.

Men with Klinefelter syndrome (KS) develop hypergonadotropic hypogonadism, are in need of testosterone replacement therapy (TRT), and present with a more than 4-fold increased risk of thrombosis. TRT in KS has the potential to modify thrombotic risk, but data are scarce. To assess effects of 18 months of TRT on hemostasis in KS and identify genes associated with the prothrombotic phenotype. Untreated and TRT-treated men with KS were included at baseline and matched to healthy controls. TRT was initiated in untreated KS and all groups were reassessed after 18 months of follow-up. Thrombin generation was evaluated with or without thrombomodulin, and fibrin clot lysis was evaluated by turbidity measurements. RNA expression was assessed in blood, fat, and muscle tissue of patients with TRT-treated KS and controls. Thrombin generation with thrombomodulin was slightly increased in untreated KS, but overall KS was not associated with a hypercoagulable state. KS presented with fibrinolytic impairment associated with higher body fat and higher levels of fibrinogen. Eighteen months of TRT in KS was associated with a reduction in body fat and fibrinogen, attenuating the prothrombotic profile. The expression of ENPP4 was higher in men with KS and served as a key player among a group of genes associated with impaired fibrinolysis. KS is associated with a specific expression profile contributing to fibrinolytic impairment and increased thrombotic risk in the patients. TRT in patients with KS has the potential for alleviating the prothrombotic phenotype, in particular by reducing body fat and fibrinogen.

Insulin-like Factor 3, Basal and Human Chorionic Gonadotropin-Stimulated Testosterone as Biomarkers to Predict the Effect of Testosterone Replacement in Testicular Cancer Survivors With Mild Leydig Cell Insufficiency

IntroductionMild Leydig cell insufficiency affects a substantial proportion of testicular cancer survivors. Previous studies have not shown a beneficial effect of testosterone replacement therapy, however, with a pronounced interindividual effect. Thus, biomarkers identifying the subgroups that might benefit are wanted. We aimed to determine if insulin-like factor 3 (INSL3), basal and human chorionic gonadotropin (hCG)-stimulated testosterone can predict the effect of testosterone replacement therapy in testicular cancer survivors with mild Leydig cell insufficiency. Patients and MethodsWe randomized adult testicular cancer survivors with mild Leydig cell insufficiency 1:1 to 12 months of transdermal testosterone replacement therapy (Tostran gel 2%) or placebo. INSL3, basal, and hCG-stimulated testosterone were measured at baseline. Outcomes (glucose, insulin, HbA1C, lipids, blood pressure, and body composition) were measured at baseline, 6 and 12 months. We applied a linear mixed-effect model comparing patients receiving testosterone with placebo in subgroups by biomarker. ResultsWe included and randomized 69 patients between October 2016 and February 2018. Patients with INSL3 and hCG-stimulated testosterone concentrations below the median had a -1.7 kg (95% CI: -3.1, -0.4) and -2.0 kg (95% CI: -3.5, -0.6) change in fat mass after 12 months of testosterone replacement therapy compared with placebo. This was not the case in patients with INSL3 and hCG-stimulated testosterone above the median. We did not find any effect of these biomarkers on glucose, insulin, HbA1c, or lipids. ConclusionPatients with INSL3 and hCG-stimulated testosterone concentrations below the median had decreased fat mass after 12 months of testosterone replacement therapy compared with placebo. It should be evaluated in larger trials if these biomarkers can be used as predictive markers identifying testicular cancer patients with mild Leydig cell insufficiency who might benefit from testosterone substitution.

Effect of 12-months testosterone replacement therapy on bone mineral density and markers of bone turnover in testicular cancer survivors – results from a randomized double-blind trial

Background Testicular cancer survivors (TCS) are at risk of Leydig cell insufficiency, which is a condition characterized by elevated luteinising hormone (LH) in combination with low levels of testosterone. It has been suggested that this condition is associated with impaired metabolic profile and low bone mineral density (BMD). The primary aim of the randomized double-blind trial NCT02991209 was to evaluate metabolic profile after 12-months testosterone replacement therapy (TRT) in TCS with mild Leydig cell insufficiency. Here we present the secondary outcomes of changes in BMD and markers of bone turnover. Methodology In total, 69 TCS with mild Leydig cell insufficiency were randomized 1:1 to 12 months TRT (n = 35) (Tostran, gel, 2%, applied transdermally, with a maximum daily dose of 40 mg) or placebo (n = 34). BMD and markers of bone turnover were evaluated at baseline, after 6- and 12-months TRT, and 3-months post-treatment. Linear mixed effects models were used to analyse changes in BMD, N-terminal propeptide of type 1 procollagen (P1NP) and C-terminal telopeptide of type I collagen (CTX). Results After 12 months treatment, TRT was not associated with a statistically significant difference in BMD compared to placebo; total body BMD: 0.01 g/cm2 (95% confidence interval (CI): −0.01 − 0.02), BMD of the lumbar spine: 0.01 g/cm2, (95% CI: −0.01–0.03), BMD of the left femoral neck: 0.00, (95% CI: −0.01–0.02). TRT was associated with a small but statistically significant increase in P1NP: 11.65 µg/L (95% CI: 3.96, 19.35), while there was no difference in CTX. Conclusion 12 months of TRT did not change BMD, while there was as small and clinically irrelevant increase in P1NP compared to placebo in TCS with mild Leydig cell insufficiency. The findings need validation in a larger cohort.

Testosterone replacement therapy is associated with increased odds of Achilles tendon injury and subsequent surgery: a matched retrospective analysis

BackgroundPrescription of testosterone replacement therapy (TRT) has increased in the United States in recent years, and though anabolic steroids have been associated with tendon rupture, there is a paucity of literature evaluating the risk of Achilles tendon injury with TRT. This study aims to evaluate the associative relationship between consistent TRT, Achilles tendon injury, and subsequent surgery.MethodsThis is a one-to-one matched retrospective cohort study utilizing the PearlDiver database. Records were queried for patients aged 35–75 who were prescribed at least 3 consecutive months of TRT between January 1, 2010 and December 31, 2019. Achilles tendon injuries and subsequent surgeries were identified using ICD-9, ICD-10, and CPT billing codes. Multivariable logistic regression was used to compare odds of Achilles tendon injury, Achilles tendon surgery, and revision surgery, with a p-value < 0.05 representing statistical significance.ResultsA sample of 423,278 patients who filled a TRT prescription for a minimum of 3 consecutive months was analyzed. The 2-year incidence of Achilles tendon injury was 377.8 (95% CI, 364.8–391.0) per 100,000 person-years in the TRT cohort, compared to 245.8 (95% CI, 235.4–256.6) in the control (p < 0.001). The adjusted analysis demonstrated TRT to be associated with a significantly increased likelihood of being diagnosed with Achilles tendon injury (aOR = 1.24, 95% CI, 1.15–1.33, p < 0.001). Of those diagnosed with Achilles tendon injury, 287/3,198 (9.0%) of the TRT cohort subsequently underwent surgery for their injury, compared to 134/2,081 (6.4%) in the control cohort (aOR = 1.54, 95% CI, 1.19–1.99, p < 0.001).ConclusionsThere is a significant association between Achilles tendon injury and prescription TRT, with a concomitantly increased rate of undergoing surgical management. These results provide insight into the risk profile of TRT and further research into the science of tendon pathology in the setting of TRT is an area of continued interest.

Testosterone Replacement Therapy in Chronic Kidney Disease Patients

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

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

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

Klinefelter Bone Microarchitecture Evolution with Testosterone Replacement Therapy.

Klinefelter Syndrome (KS) patients, defined by a 47 XXY karyotype, have increased risk of fragility fractures. We have assessed bone microarchitecture by high resolution peripheral quantitative CT (HR-pQCT) at the radius and tibia in young KS patients, naïve from testosterone replacement therapy (TRT). Areal bone mineral density (BMD) and body composition were assessed by dual X-ray absorptiometry (DXA). Total testosterone (tT) was measured at baseline. Bone measurements have been repeated after 30months of TRT. We enrolled 24 KS patients and 72 age-matched controls. KS patients were (mean ± SD) 23.7 ± 7.8year-old. KS patients had significantly lower relative appendicular lean mass index (RALM) and lower aBMD at spine and hip than controls. Ten patients (42%) had low tT level (≤ 10.4nmol/L). At baseline, we observed at radius a marked cortical (Ct) impairment reflected by lower Ct.area, Ct.perimeter, and Ct.vBMD than controls. At tibia, in addition to cortical fragility, we also found significant alterations of trabecular (Tb) compartment with lower trabecular bone volume (BV/TV) and Tb.vBMD as compared to controls. After 30months of TRT, 18 (75%) KS patients were reassessed. Spine aBMD and RALM significantly increased. At radius, both cortical (Ct.Pm, Ct.Ar, Ct.vBMD, Ct.Th) and trabecular (Tb.vBMD) parameters significantly improved. At tibia, the improvement was found only in the cortical compartment. Young TRT naïve KS patients have inadequate bone microarchitecture at both the radius and tibia, which can improve on TRT.

Efficacy of testosterone replacement therapy on pain in hypogonadal men with chronic pain syndrome: A subanalysis of a prospective randomised controlled study in Japan (EARTH study).

The present study investigated the efficacy of 6months of testosterone replacement therapy (TRT) on chronic pain syndrome in late-onset hypogonadal (LOH) men. Sixty hypogonadal patients with chronic pain syndrome (31 patients in TRT group and 29 controls) were extracted from a previous randomised controlled study in Japan. Chronic pain was evaluated based on bodily pain (BP) subscale of Short-form (36) Health Survey (SF-36), and patients with a score of 50.0 or less were defined as suffering from chronic pain. SF-36 scores, Aging Male Symptoms (AMS) scale, international prostatic symptoms score (IPSS) and prostate-specific antigen (PSA) levels at baseline and a 6-month visit for the two groups were collected and compared. There were no statistically significant differences in baseline backgrounds between the two groups. Six-month TRT could contribute to significant improvements in BP, mental health of SF-36 and sleep disturbance (AMS question 4). Though the PSA level in the TRT group also significantly elevated at 6months, the increase was not clinically significant. No significant improvements were evident in any characteristics in the controls. In conclusion, 6-month TRT can improve pain and some aspects of quality of life in LOH men with chronic pain.

SUN-LB039 Novel Use of Thromboelastography (TEG) to Investigate the Prothrombotic Effects of Testosterone Replacement Therapy (TRT) for Androgen Deficiency (AD) Established with Diagnostic Rigor (DR)

Background Endocrine Society recommends ≥2 low bioavailable (BAT) or free Testosterone (T) levels in the early AM by tandem mass spectroscopy to establish AD with DR. They also advise against TRT with a recent history of vascular events (VEs). Data from our center affirm these recommendations. TRT increased VE risk four-fold without DR versus with DR, and eight-fold with a history of recent VEs versus without, suggesting that inappropriate TRT might provoke VEs in the absence of AD, or with high vascular risk. The etiopathogenesis of VEs on TRT is not understood, nor is it known if TRT induces a prothrombotic state, but two putative mechanisms might be involved. First, T increases platelet receptors for thromboxane A2, a potent vasoconstrictor and platelet aggregant. Second, T is aromatized to estradiol (E2), a potent activator of the clotting cascade, inhibitor of antithrombin III, and platelet aggregant. Objective To determine (a) whether TEG, a clinically validated tool for assessing platelet function and clotting can be used to identify a prothrombotic state during TRT for AD proven with DR, and (b) if changes are related to estradiol levels. Methods Male veterans >18 years of age referred for suspected AD, and with no contraindications to TRT, were recruited for the study. After AD was established according to guidelines, blood samples were drawn for TEG and E2 before TRT initiation and after 3 months of TRT, and the following TEG parameters were assessed: Reaction Time for initial fibrin formation (R), reflecting the clotting cascade, Kinetic Time for fibrin cross linkage (K), reflecting fibrinogen and platelet number, Angle (α), reflecting the speed of clot strengthening, and Maximum Amplitude (MA), reflecting platelet function. Results In 7 subjects (median age 64 [IQR 38,68]), on TRT for 88±5d (Mean±SE), calculated BAT increased from 82±17ng/dl to 143±32ng/dl (p=0.046), but E2 did not change significantly (14.3±2.5 vs 19.6±4.2pg/ml, p=0.4). R increased 17% on TRT compared to before (∆=0.9±0.2min, p=0.012), showing that time to initial fibrin formation was prolonged, while remaining within the normal range. However, there was no significant change in K, α, or MA. ConclusionsOur data, based on the novel use of TEG to study a potentially prothrombotic effect of TRT, show for the first time that TRT inhibits, not activates the kinetics of the enzymatic process of coagulation. In other words, appropriate TRT had no prothrombotic effect in an admittedly small number of patients with AD established with DR. This accords with both the four-fold decrease in VEs we observed earlier on TRT prescribed appropriately with DR, as well as some prior reports of a lower risk of VEs on TRT. It is conceivable that TRT might induce a prothrombotic state when prescribed inappropriately in the absence of AD, given that many studies showing that TRT increases VE risk have not employed DR to establish AD conclusively. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Changes in left ventricular repolarization after short-term testosterone replacement therapy in hypogonadal males

Background and aimEvidences suggest that androgen deficiency is associated with sudden cardiac death (SCD). Our purpose was to analyse some electrocardiographic (ECG) markers of repolarization phase in hypogonadal patients either at baseline or after testosterone replacement therapy (TRT).Patients and MethodsBaseline and after 6 months of testosterone replacement therapy, 14 hypogonadal patients and 10 age-matched controls underwent a short-term ECG recordings at rest and immediately after a maximal exercise test. The following ECG parameters have been collected: QTe (the interval between the q wave the end of T wave), QTp (the interval between the q wave and the peak of T wave), and Te (the interval between the peak and the end of T wave).ResultsAt baseline, in the hypogonadal patients, corrected QTe and QTp values were longer at rest than in the controls at rest (p < 0.05), whereas, during the recovery phase, only the QTp remained significantly longer (p < 0.05). After TRT, hypogonadal patients showed an improvement only in Te (p < 0.05). Conversely, any difference between hypogonadal patients and control subjects was found with respect to the markers of temporal dispersion of repolarization phases, except for a worse QTp → Te coherence (p = 0.001) obtained during the recovery phase.ConclusionsIn conclusion, at rest, hypogonadal patients suffer from a stable increase in the myocardial repolarization phase without an increase in its temporal dispersion and, hence, the SCD risk seems to be low.

Endocrine and psychological aspects of sexual dysfunction in Klinefelter patients.

Klinefelter syndrome is a frequent cause of hypogonadism, but despite hundreds of publications on different aspects of Klinefelter syndrome, only a few studies dealt with sexual dysfunction. In particular, testosterone is critical for various aspects of sexual response, but its role on sexuality in Klinefelter syndrome patients is debatable and no studies have evaluated the efficacy of testosterone treatment on sexual dysfunction in these subjects. Furthermore, the impact of psychological and relational aspects on sexual function of Klinefelter syndrome subjects is poorly defined. In this study, we aimed to determine the presence and type of sexual dysfunctions in Klinefelter syndrome subjects; to correlate them with testosterone levels and psychosexological and relational domains; and to evaluate the effects of testosterone therapy. We studied 62 non-mosaic naïve Klinefelter syndrome patients and 60 age-matched controls by means of medical history, psychosexological history, 15-item International Index of Erectile Function questionnaire, endocrine assessment, and dynamic penile color Doppler ultrasound. Twenty-five hypogonadal Klinefelter syndrome patients were studied after 6months of testosterone replacement therapy. Klinefelter syndrome subjects have reduced 15-item International Index of Erectile Function scores regarding sexual desire, intercourse satisfaction, and overall satisfaction with respect to controls, and these aspects were significantly associated with testosterone levels. Klinefelter syndrome subjects had also higher prevalence of erectile dysfunction, but no relation with testosterone levels was evident. A high prevalence of a range of psychological disturbances was present in Klinefelter syndrome subjects with erectile dysfunction with respect to those without erectile dysfunction. No statistical difference in the prevalence of premature and delayed ejaculation was observed between Klinefelter syndrome and control subjects. Testosterone replacement therapy improved sexual desire, intercourse satisfaction, and overall satisfaction scores, but had no effect on erectile function. Penile color Doppler ultrasound was normal in all subjects. This study shows that sexual dysfunction in Klinefelter syndrome is multifactorial and related only in part to hypogonadism and largely to psychological disturbances. Evaluation and therapy of sexual dysfunction should include a combined andrological and psychosexological approach.

Endothelial dysfunction, insulin resistance and inflammation in congenital hypogonadism, and the effect of testosterone replacement.

Patients with hypogonadism have poor cardiovascular and metabolic outcomes, and the effect of testosterone replacement therapy (TRT) is not clear. We investigated the presence of inflammation, insulin resistance and endothelial dysfunction in an unconfounded population of congenital hypogonadotrophic hypogonadism (CHH) and the effect of TRT on these subjects. A total of 60 patients with CHH (mean age 21.82±2.22 years) and 70 healthy control subjects (mean age 21.32±1.13 years) were enrolled. The demographic parameters, Asymmetric dimethylarginine (ADMA), TNF-like weak inducer of apoptosis (TWEAK), high sensitive C reactive protein (hs-CRP) and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured before and after TRT. The patients had higher Waist Circumferences (WC) (p=0.009), Diastolic Blood Pressures (p=0.02), Triglycerides (p=0.03), ADMA, insulin and HOMA-IR levels (p<0.001 for all) and lower TWEAK levels (p<0.001), compared to the healthy controls. After 5.56 ± 2.04 months of TRT, the patients had significantly elevated systolic blood pressures (p=0.01), body mass indexes and WC (p<0.001 and p=0.001 respectively) and decreased total and HDL cholesterol levels (p=0.032 and p<0.001 respectively). ADMA levels significantly increased (p=0.003), while the alterations in TWEAK, hsCRP and HOMA-IR were not significant. The results of the present study show that endothelial dysfunction, inflammation and insulin resistance are prevalent even in the very young subjects with CHH, who have no metabolic or cardiac problems at present. This increased cardiometabolic risk however, do not improve but even get worse after six months of TRT. Long term follow-up studies are warranted to investigate the unfavorable cardiometabolic effects of TRT.

Comprehensive evaluation of androgen replacement therapy in aging Japanese men with late-onset hypogonadism

Objective: This study assessed the efficacy and safety of testosterone replacement therapy (TRT) in aging Japanese men with late-onset hypogonadism (LOH).Methods: This study included 50 (median age: 57.7 years) Japanese men with LOH, who were consecutively enrolled and treated with TRT for at least six months at our institution. We evaluated the following measurements before and after six months of treatment with TRT as follows: blood tests, prostate volume, residual urine volume, self-ratings for International Index of Erectile Function 5 (IIEF-5), International Prostate Symptom Score (IPSS), Self-Rating Depression Scale (SDS), Aging Male Symptom (AMS) and the Medical Outcomes Study 8-item Short-Form health survey (SF-8).Results: Following six months of TRT, the levels of testosterone, red blood cells, hemoglobin and hematocrit were significantly increased from baseline, while total cholesterol level was significantly decreased from baseline. Furthermore, TRT led to a significant increase in IIEF-5 score and a significant decrease in IPSS score. Of 30 men who were diagnosed with depression at baseline, only 11 men (36.7%) were still suffering from depression after TRT, and SDS scores were significantly decreased from baseline at month six. Treatment with TRT led to a significant decrease in all scores of the AMS scale as well as a significant improvement in all scores of the SF-8 survey, with the exception of the bodily pain score.Conclusion: These findings suggest that TRT is an effective and safe treatment for aging Japanese men with LOH. TRT improved depressive symptoms as well as health-related quality of life.

Testosterone replacement therapy in men with prostate cancer after proton therapy.

208 Background: Testosterone replacement therapy (TRT) in patients previously treated for prostate cancer is controversial. We analyzed biochemical relapse and sexual function in patients treated for prostate cancer with proton therapy (PT) at our institution who were later treated with TRT for hypogonadism. Methods: We reviewed the medical records of 27 patients with biopsy-proven, localized prostate cancer treated with definitive proton therapy (PT) at our institution between 2006 and 2012. Each patient had hypogondal symptoms and low-serum testosterone and received testosterone replacement after PT. Biochemical failure was defined by the Phoenix definition. Sexual function was reported using patient-reported data from the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. Rates of sexual potency were also reported. Results: Twenty-three patients were included in the present analysis. The median follow-up duration was 38 months after PT and 14 months after initiation of TRT. After one to six months on TRT, the median serum testosterone level in this patient cohort increased from 238 to 497. No patient experienced a biochemical failure. The median prostate-specific antigen (PSA) did not significantly rise during the follow-up period. EPIC sexual summary, sexual function, and sexual bother scores all increased after initiation of TRT. The median sexual bother scores increased from 43.8 before TRT to 59.4 after 7 or more months of TRT. The median sexual summary scores improved from 50 to 61.8 and the median sexual function scores improved from 41.7 to 53 over the same time. Sexual potency also increased after TRT initiation from 50% to 68%, 7 or more months after TRT. Conclusions: For patients diagnosed with hypogonadism who were previously treated for prostate cancer, cautious use of testosterone replacement therapy does not appear to increase the risk of biochemical failure or increase PSA. Sexual function may improve to approximate pre-radiation levels in some cases. A prospective trial with long-term follow up is required to better support our findings.

12-Month Observation of Testosterone Replacement Effectiveness in a General Population of Men

Background: Testosterone decline becomes more prevalent as men age and symptomatic testosterone deficiency is associated with potentially serious comorbidities. Despite limitations, registries can provide an opportunity to accumulate data regarding disease management in a typical patient population, including diagnosis, treatment, and outcomes. Materials and Methods: The Testim Registry in the United States (TRiUS) was a prospective, 12-month, observational cohort registry of men prescribed Testim® (1% testosterone gel; Auxilium Pharmaceuticals, Inc.) for the first time; patients previously on other forms of testosterone replacement therapy (TRT) were eligible to participate in the study as well. The registry recorded total testosterone (TT) and free testosterone (FT) levels, prostate-specific antigen (PSA), sexual function, mood/depression, and cardiometabolic and anthropometric criteria before and after TRT. Changes over time were analyzed by analysis of variance, and linear regression and Pearson product-moment correlation coefficients were used to examine relationships between variables. Results: At baseline, 849 patients from 72 sites were enrolled, with 743 of 849 started on 5 g gel/day (50 mg testosterone/day) and 106 of 849 started on 10 g gel/day (100 mg testosterone/day). Mean TT and FT levels increased significantly after 3 months of TRT (TT level, 16.8 ± 9.87 nmol/L [485 ± 284 ng/dL], P < 0.001; FT level, 286.3 ± 224.9 pmol/L [82.5 ± 64.8 pg/mL], P < 0.001) and were maintained at eugonadal levels. Mean PSA levels increased significantly (P = 0.004) from 1.12 ± 1.11 μg/L (1.12+1.11 ng/mL) at baseline to 1.26 ± 1.22 μg/L (1.26 ± 1.22 ng/mL) after 12 months of TRT, although changes were well within guidelines (< 1.4 μg/L/year increase). Significant improvements were seen in sexual function and mood/depression at 3 months and in metabolic parameters at 12 months. Conclusion: Testosterone deficiency symptoms improved with TRT use in men; sexual function and mood/depression improvements were seen before metabolic improvements. Prostate-specific antigen levels increased, although increases were within guideline-determined safety limits.

Testosterone replacement elevates the serum uric acid levels in patients with female to male gender identity disorder

Gender identity disorder (GID) results from a disagreement between a person's biological sex and the gender to which he or she identifies. With respect to the treatment of female to male GID, testosterone replacement therapy (TRT) is available. The uric acid (UA) level can be influenced by testosterone; however, the early effects and dose-dependency of TRT on the serum UA concentration have not been evaluated in this population. We herein conducted a dose-response analysis of TRT in 160 patients with female to male GID. The TRT consisted of three treatment groups who received intramuscular injections of testosterone enanthate: 125 mg every two weeks, 250 mg every three weeks and 250 mg every two weeks. Consequently, serum UA elevation was observed after three months of TRT and there was a tendency toward testosterone dose-dependency. The onset of hyperuricemia was more prevalent in the group who received the higher dose. We also demonstrated a positive correlation between increased levels of serum UA and serum creatinine. Since the level of serum creatinine represents an individual's muscle volume and the muscle is a major source of purine, which induces UA upregulation, the serum UA elevation observed during TRT is at least partially attributed to an increase in muscle mass. This is the first study showing an association between serum UA elevation and a TRT-induced increase in muscle mass. The current study provides important information regarding TRT for the follow-up and management of the serum UA levels in GID patients.

Testosterone replacement therapy among elderly males: the Testim Registry in the US (TRiUS)

Background:Testosterone levels naturally decline with age in men, often resulting in testosterone deficiency (hypogonadism). However, few studies have examined hypogonadal characteristics and treatment in older (≥65 years) men.Objective:To compare data at baseline and after 12 months of testosterone replacement therapy (TRT) in hypogonadal men ≥65 vs <65 years old. Data for participants 65–74 vs ≥75 years old were also compared.Methods:Data were from TRiUS (Testim Registry in the United States), which enrolled 849 hypogonadal men treated with Testim® 1% (50–100 mg testosterone gel/day) for the first time. Anthropometric, laboratory, and clinical measures were taken at baseline and 12 months, including primary outcomes of total testosterone (TT), free testosterone (FT), and prostate-specific antigen (PSA) levels. Comparisons of parameters were made using Fisher’s exact test or analysis of variance. Nonparametric Spearman’s ρ and first-order partial correlation coefficients adjusted for the effect of age were used to examine bivariate correlations among parameters.Results:Of the registry participants at baseline with available age information, 16% (133/845) were ≥65 years old. They were similar to men <65 years old in the duration of hypogonad-ism prior to enrollment (∼1 year), TT and FT levels at baseline, TT and FT levels at 12-month follow-up, and in reported compliance with treatment. Older patients were more likely to receive lower doses of TRT. PSA levels did not statistically differ between groups after 12 months of TRT (2.18 ± 2.18 ng/mL for ≥65 vs 1.14 ± 0.84 ng/mL for <65 years old, P = 0.1). Baseline values for the >75-year-old subcohort were not significantly different from subcohorts aged 65–74 years and <65 years.Conclusion:Hypogonadal men ≥65 years old showed significant benefit from TRT over 12 months, similar to that found for hypogonadal men <65 years old. TRT was well tolerated in older patients, successfully increased testosterone level regardless of age, and did not significantly increase PSA levels in older men.

Changes in Prostate Specific Antigen in Hypogonadal Men After 12Months of Testosterone Replacement Therapy: Support for the Prostate Saturation Theory

Changes in Prostate Specific Antigen in Hypogonadal Men After 12Months of Testosterone Replacement Therapy: Support for the Prostate Saturation Theory