Testosterone supplementation increases red blood cell susceptibility to oxidative stress, decreases membrane deformability, and decreases survival after cold storage and transfusion.

BACKGROUND: Blood collection from donors on testosterone therapy (TT) is restricted to red blood cell (RBC) concentrates to avoid patient exposure to supraphysiological testosterone (T). The objective of this study was to identify TT-related changes in RBC characteristics relevant to transfusion effectiveness in patients. STUDY DESIGN: This was a two-part study with cohorts of patients and blood donors on TT. In part 1, we conducted longitudinal evaluation of RBCs collected before and at three time points after initiation of T. RBC assays included storage and oxidative hemolysis, membrane deformability (elongation index), and oximetry. In part 2, we evaluated the fate of transfused RBCs from TT donors in immunodeficient mice and by retrospective analyses of NIH's vein-to-vein databases. RESULTS: TT increased oxidative hemolysis (1.45-fold change) and decreased RBC membrane deformability. Plasma free testosterone was positively correlated with oxidative hemolysis (r = .552) and negatively correlated with the elongation index (r = -.472). Stored and gamma-irradiated RBCs from TT donors had lower posttransfusion recovery in mice compared to controls (41.6 ± 12 vs. 55.3 ± 20.5%). Recipients of RBCs from male donors taking T had 25% lower hemoglobin increments compared to recipients of RBCs from non-TT male donors, and had increased incidence (OR, 1.80) of requiring additional RBC transfusions within 48 h of the index transfusion event. CONCLUSIONS: TT is associated with altered RBC characteristics and transfusion effectiveness. These results suggest that clinical utilization of TT RBCs may be less effective in recipients who benefit from longer RBC survival, such as chronically transfused patients.

Testosterone therapy reduces insulin resistance in men with adult-onset testosterone deficiency and metabolic syndrome. Results from the Moscow Study, a randomized controlled trial with an open-label phase.

AIMS: To describe changes in homeostasis model assessment of insulin resistance index (HOMA-IR) following testosterone therapy in men with hypogonadism and metabolic syndrome (MetS). MATERIALS AND METHODS: A randomized, placebo-controlled, double-blind randomized controlled trial (RCT) comprising 184 men with MetS and hypogonadism (testosterone undecanoate [TU]: 113 men, placebo: 71 men) was conducted. This was followed by an open-label phase in which all men were given TU. We focused on men who were not receiving antiglycaemic agents (TU: 81 men; placebo: 54 men) as these could affect HOMA-IR. Inter-group comparison of HOMA-IR was restricted to the RCT (30 weeks), whilst intra-group comparison was carried out on men provided TU during the RCT and open-label phases (study cohort) and men given placebo during the RCT and then switched to TU during the open-label phase (confirmatory cohort). Regression analysis was performed to identify factors associated with change in HOMA-IR (∆HOMA-IR). RESULTS: The median HOMA-IR was significantly reduced at almost every time point (after 18 weeks) compared to baseline in men receiving TU in both the study and confirmatory cohorts. There was a significant decrease in median values of fasting glucose (30 weeks: -2.1%; 138 weeks: -4.9%) and insulin (30 weeks: -10.5%; 138 weeks: -35.5%) after TU treatment. Placebo was not associated with significant ∆HOMA-IR. The only consistent predictor of HOMA-IR decrease following TU treatment was baseline HOMA-IR (r2 ≥ 0.64). CONCLUSIONS: Baseline HOMA-IR predicted ΔHOMA-IR, with a greater percentage change in insulin than in fasting glucose. In men with MetS/type 2 diabetes (T2DM) not on antiglycaemic therapy, improvements in HOMA-IR may be greater than suggested by change in fasting glucose. Our results suggest that hypogonadism screening be included in the management of men with MetS/T2DM.

Testosterone and resistance training improved physical performance and reduced fatigue in frail older men: 1 year follow-up of a randomized clinical trial.

OBJECTIVE: To improve health conditions among hypogonadal men ≥70 years of age using testosterone undecanoate (TU) injections, progressive strength training, and oral supplements of vitamin D, calcium, and protein. METHODS: This study is a 1-year follow-up of a double-blind RCT lasting 20 weeks, including 148 older men ≥70 years old with low testosterone levels and mobility problems. During 52 weeks, 4 groups received either testosterone therapy (TU) or progressive resistance training (Training), both (Combo), or no intervention (Controls). Physiotherapists supported the training groups until week 20, while these participants continued trained on their own during weeks 21 to 52. The main outcome measure was the 30-s chair stand test. RESULTS: The following numbers of participants completed the trial: 20 (Combo), 20 (Controls), 24 (TU), and 14 (Training). When examining 30-s chair stand test performance within each group at baseline, and at weeks 4, 20 and 52, only the Combo group improved (p = 0.001, Friedman Test). Compared to controls, only the Combo group experienced reduced fatigue and tiredness (p < 0.05). CONCLUSIONS: Fifty-two weeks of testosterone supplementation combined with progressive resistance training may enhance physical performance, alleviate fatigue, and had no notable detrimental impacts among males aged ≥70 suffering from mobility issues and testosterone insufficiency.Trial registration - Clinical Trials NCT02873559.

Testosterone therapy over 60 months improves aging male symptoms scores in all men with adult-onset testosterone deficiency.

OBJECTIVE: We evaluated change (Δ) in AMSS in men with adult-onset testosterone deficiency (TD) on/not on testosterone undecanoate (TU) by analysing a registry of men with adult-onset TD. METHODS: Analyses were performed using non-parametric statistics to determine ΔAMSS at 6-12 monthly intervals in men on/not on TU and movement in AMSS. Factors predicting ΔAMSS were established via linear/multiple regression. RESULTS: TU was significantly associated with lower AMSS values compared with that at baseline/prior assessment during the initial 42 months treatment; 259 of the 260 men showed improvement. In the 361 men not on TU, AMSS values increased during 60 months of follow-up compared with that at baseline/prior assessment; improvement after 60 months was evident in 1 man, whilst AMSS remained the same or worsened in 213 and 147 men, respectively. In men on TU, baseline AMSS was inversely associated with ΔAMSS (R2 = 0.97), with no other factors reaching significance. Baseline AMSS, age, serum total testosterone (TT), waist circumference (WC), and diastolic blood pressure (BP) were associated with ΔAMSS in men not on TU. DISCUSSION: We show that TU was associated with lower AMSS in men with adult-onset TD whilst non-treatment led to increased values. Baseline AMSS values inversely predicted ΔAMSS in both groups.

Persistent vaginal bleeding during gender-affirming hormone therapy in transgender men.

PURPOSE: While it is common for menstrual cycles to cease within the initial 6 months of treatment, there are instances where some transgender men may not experience this cessation. We analyzed transgender men undergoing gender-affirming hormone therapy (GAHT) with testosterone who experienced breakthrough bleeding in order to identify the factors associated with this condition. METHODS: In this case-control study, 24 transgender men in the case group and 48 in the control group were assessed for clinical, sociodemographic, hormonal, and body composition variables using dual-energy X-ray absorptiometry. All participants had been on GATH for at least 6 months. RESULTS: A few transgender men experienced persistent breakthrough bleeding, which was associated with decreased testosterone levels and free androgen index (FAI) compared with controls (p = 0.002 and p = 0.008, respectively). Among individuals with breakthrough bleeding, 50% had testosterone levels below the lowest tertile calculated for the sample, compared with 18.8% on controls (p = 0.007). After therapy adjustment, testosterone levels increased compared with the values obtained in the initial bleeding episode (p = 0.031). Eight transgender men required the addition of an oral progestogen to achieve amenorrhea, and these individuals had higher BMI than those in whom the adjustment of the parenteral testosterone dose was adequate (p = 0.026). A univariate prevalence ratio analysis revealed a negative association of persistent bleeding with testosterone levels (p = 0.028) and FAI levels (p = 0.019). CONCLUSION: Higher BMI and lower levels of testosterone and FAI were the main factors associated with breakthrough bleeding in transgender men.

Arrhythmogenic substrate elimination for safe testosterone therapy in symptomatic Brugada syndrome patients.

BACKGROUND: Brugada Syndrome (BrS) is a cardiogenetic disease known for its association with sudden cardiac death (SCD) in individuals with structurally normal hearts. The prevalence of BrS is higher in males, who also face a greater risk of SCD. Its higher prevalence and worse outcome in male subjects may be due to testosterone effects on ion channels expression and function. The influence of testosterone on cardiac action potentials, both genomically and non-genomically, underscores its potential role in unmasking the syndrome and triggering life-threatening arrhythmias. Notably, testosterone replacement therapy (TRT), used for hypogonadism and gender reassignment, has been linked to BrS unmasking. The role of epicardial ablation in symptomatic BrS patients where hormonal therapy cannot be discontinued is unknown. METHODS AND RESULTS: In this study we describe the first two cases of substrate mapping and ablation in BrS patients experiencing arrhythmic events while on TRT. In both cases, high-density epicardial mapping revealed abnormal areas of prolonged and fragmented electrograms in the right ventricular (RV) outflow tract and anterior wall. These abnormalities were completely abolished by radiofrequency ablation (RFA). After ablation, both patients showed a persistent normalization of the ECG and were free from ventricular arrhythmias at follow-up, despite ongoing TRT. CONCLUSION: RFA can be considered as a therapeutic option in symptomatic BrS patients with a high-risk profile who cannot discontinue TRT, being essential for restoring their normal physiology or preserving their sexual identity. As testosterone use is increasing, further studies are warranted to define a standardized diagnostic and therapeutic strategy in this specific subset of BrS patients.

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

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

Luteinizing Hormone Suppression Profiles in Men Treated With Exogenous Testosterone.

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

Testosterone does not affect lower urinary tract symptoms while improving markers of prostatitis in men with benign prostatic hyperplasia: a randomized clinical trial.

PURPOSE: Benign Prostatic Hyperplasia (BPH) is a result of prostate inflammation, frequently occurring in metabolic syndrome (MetS). Low testosterone is common in MetS. A randomized clinical trial was designed to evaluate if 24 weeks of testosterone therapy (TTh) in BPH men with MetS and low testosterone improve urinary symptoms and prostate inflammation. METHODS: One-hundred-twenty men with MetS waitlisted for BPH surgery were enrolled. They were categorized into normal testosterone (TT ≥ 12 nmol/L and cFT ≥ 225 pmol/L; n = 48) and testosterone deficient (TD) (TT < 12 nmol/L and/or cFT < 225 pmol/L; n = 72) then randomized to testosterone gel 2% (5 g/daily) or placebo for 24 weeks. At baseline and follow-up, questionnaires for urinary symptoms and trans-rectal ultrasound were performed. Prostate tissue was collected for molecular and histopathological analyses. RESULTS: No differences in the improvement of urinary symptoms were found between TTh and placebo (OR [95% CI] 0.96 [0.39; 2.37]). In TD + TTh, increase in prostate but not adenoma volume was observed (2.64 mL [0.07; 5.20] and 1.82 mL [- 0.46; 0.41], respectively). Ultrasound markers of inflammation were improved. In a subset of 61 men, a hyper-expression of several pro-inflammatory genes was found in TD + placebo when compared with normal testosterone. TTh was able to counteract this effect. For 80 men, the inflammatory infiltrate was higher in TD + placebo than in normal testosterone (0.8 points [0.2; 1.4]) and TD + TTh men (0.9 points [0.2; 1.5]). CONCLUSIONS: Twenty-four weeks of TTh in TD men with BPH and MetS improves ultrasound, molecular and histological proxies of prostate inflammation. This does not result in symptom improvement.

Efficacy of short-term induction therapy with low-dose testosterone as a diagnostic tool in the workup of delayed growth and puberty in boys.

PURPOSE: Constitutional delay of growth and puberty (CDGP) represents the most frequent cause of delayed puberty in males, sharing some clinical features with growth hormone deficiency (GHD) and isolated hypogonadotropic hypogonadism (IHH). Short-term induction therapy (SIT) has been approved for the induction of puberty in CDGP. We aim to investigate the efficacy of SIT with transcutaneous testosterone gel (TTG) or intramuscular testosterone therapy (IMTT) in a cohort of CDGP subjects, compared to clinical observation. Furthermore, we aim to evaluate the role of SIT as a diagnostic tool to differentiate CDGP from GHD and IHH subjects. METHODS: The retrospective study included 246 male subjects with delayed puberty. The study population was divided into three groups: TTG, IMTT, and control group (CNT). RESULTS: At 6 months observation, height velocity (HV) was significantly increased in both treated groups compared to CNT group, particularly higher in TTG than IMTT group. A significant testicular enlargement was revealed in both CNT and TTG group compared to IMTT group. Furthermore, LH value was significantly greater in TTG compared to IMTT group. IGF-1 values after SIT rose significantly in both treated groups compared to CNT group. Moreover, almost all GH provocative tests performed after SIT showed a normal GH response. CONCLUSION: SIT with TTG appears to be more effective to induce growth spurt, better tolerated and with a more physiological effect on pubertal induction compared to IMTT in CDGP population. Finally, TTG might be a useful tool in the diagnostic work up to discriminate CDGP from GHD or IHH.

Testosterone Therapy for Late-Onset Hypogonadism Improves Erectile Function: A Systematic Review and Meta-Analysis.

INTRODUCTION: Randomized controlled trials (RCTs) of testosterone therapy (TTh) for late-onset hypogonadism are systematically reviewed and a meta-analysis to assess the efficacy of TTh in improving erectile function is performed. METHODS: The PubMed, Cochrane Library, and Web of Science databases were searched to identify RCTs published from 2007. RCTs that assessed erectile function using the erectile function domain of the International Index of Erectile Function (IIEF-EFD) were included in the meta-analysis. RESULTS: The systematic review included 18 RCTs and the meta-analysis included 6 studies that enrolled a total of 1,458 patients. The overall meta-analysis revealed that the IIEF-EFD score was significantly improved in the TTh group compared with the placebo group (mean difference 1.86; 95% confidence interval 1.01-2.72; p < 0.0001). Compared with patients receiving placebo, there was a significant improvement in the IIEF-EFD of patients who received TTh using testosterone gel, those who received TTh for over 30 weeks, and those without diabetes mellitus or metabolic syndrome. CONCLUSION: TTh achieved a significant improvement in the IIEF-EFD score of hypogonadal men compared with placebo, especially in those who received testosterone gel, were treated for over 30 weeks, and had no comorbidities.

Plasma Metabolomics Profile of "Insulin Sensitive" Male Hypogonadism after Testosterone Replacement Therapy.

Male hypogonadism is a disorder characterized by low levels of testosterone, but patients can either show normal insulin (insulin-sensitive (IS)) or over time they can become insulin-resistant (IR). Since the two groups showed different altered metabolisms, testosterone replacement therapy (TRT) could achieve different results. In this paper, we analyzed plasma from 20 IS patients with low testosterone (<8 nmol/L) and HOMAi < 2.5. The samples, pre- and post-treatment with testosterone for 60 days, were analyzed by UHPLC and mass spectrometry. Glycolysis was significantly upregulated, suggesting an improved glucose utilization. Conversely, the pentose phosphate pathway was reduced, while the Krebs cycle was not used. Branched amino acids and carnosine metabolism were positively influenced, while ß-oxidation of fatty acids (FFA) was not activated. Cholesterol, HDL, and lipid metabolism did not show any improvements at 60 days but did so later in the experimental period. Finally, both malate and glycerol shuttle were reduced. As a result, both NADH and ATP were significantly lower. Interestingly, a significant production of lactate was observed, which induced the activation of the Cori cycle between the liver and muscles, which became the main source of energy for these patients without involving alanine. Thus, the treatment must be integrated with chemicals which are not restored in order to reactivate energy production.

Plasma Metabonomics in Insulin-Resistant Hypogonadic Patients Induced by Testosterone Treatment.

Hypogonadic subjects with insulin resistance (IR) showed different metabonomic profiles compared to normo-insulinemic subjects (IS). Testosterone replacement therapy (TRT) may have a different impact on the metabolisms of those with the presence or absence of insulin resistance. We evaluated the changes in the metabolism of IR hypogonadic patients before and after 60 days of TRT. The metabonomic plasma profiles from 20 IR hypogonadal patients were recorded using ultra-high-performance liquid chromatography (UHPLC) and high-resolution mass spectrometry (HRMS). Plasma metabolites, before and after 60 days of TRT, were compared. In hypogonadic patients, carnosine, which is important for improving performance during exercise, increased. Conversely, proline and lysine-amino acids involved in the synthesis of collagen-reduced. Triglycerides decreased and fatty acids (FFAs) increased in the blood as a consequence of reduced FFA ß-oxidation. Glycolysis slightly improved, while the Krebs cycle was not activated. Gluconeogenesis (which is the main energy source for hypogonadal IR before TRT) stopped after treatment. As a consequence, lactate and acetyl CoA increased significantly. Both lactate and acetyl CoA were metabolized into ketone bodies which increased greatly, also due to leucine/isoleucine degradation. Ketone bodies were derived predominantly from acetyl CoA because the reaction of acetyl CoA into ketone bodies is catalyzed by mtHMGCoA synthase. This enzyme is inhibited by insulin, which is absent in IR patients but overexpressed following testosterone administration. Ketosis is an alternative route for energy supply and provides the same metabolic effects as insulin but at the metabolic or primitive control level, which bypasses the complex signaling pathway of insulin. After treatment, the hypogonadic patients showed clinical symptoms related to ketonuria. They presented similarly to those following a ketogenic diet, the so-called 'keto flu'. This must be taken into account before the administration of TRT to hypogonadic patients.

On the Need to Distinguish between Insulin-Normal and Insulin-Resistant Patients in Testosterone Therapy.

Male hypogonadism is a disorder characterized by low levels of the hormone testosterone and patients may also have insulin sensitivity (IS) or insulin resistance (IR), such that they show different clinical complications and different metabolic pathways. In this review, we compare metabonomic differences observed between these two groups before and after testosterone therapy (TRT) in order to obtain information on whether the two hormones testosterone and insulin are synergistic or antagonistic. IS hypogonadism uses glucose as the main biofuel, while IR activates gluconeogenesis by the degradation of branched-chain amino acids. The Krebs (TCA) cycle is active in IS but connected with glutaminolysis, while in IR the TCA cycle stops at citrate, which is used for lipogenesis. In both cases, the utilization of fatty acids for energy (ß-oxidation) is hampered by lower amounts of acetylcarnitine, although it is favored by the absence of insulin in IR. Increased free fatty acids (FFAs) are free in the blood in IS, while they are partially incorporated in triglycerides in IR. Thus, upon TRT, the utilization of glucose is increased more in IS than in IR, revealing that in IR there is a switch from preferential glucose oxidation to lipid oxidation. However, in both cases, a high production of lactate and acetyl-CoA is the final result, with these levels being much higher in IR. Lactate is used in IS in the glucose-lactate cycle between the liver and muscle to produce energy, while in IR lactate and acetyl-CoA are biotransformed into ketone bodies, resulting in ketonuria. In conclusion, the restoration of testosterone values in hypogonadism gives better results in IS than in IR patients: in IS, TRT restores most of the metabolic pathways, while in IR TRT impairs insulin, and when insulin is inactive TRT activates an ancestral molecular mechanism to produce energy. This evidence supports the hypothesis that, over time, hypogonadism switches from IS to IR, and in the latter case most of the insulin-related metabolisms are not reactivated, at least within 60 days of TRT. However, testosterone therapy in both IS and IR might be of benefit given supplementation with metabolites that are not completely restored upon TRT, in order to help restore physiological metabolisms. This review underlines the importance of using a systems biology approach to shed light on the molecular mechanisms of related biochemical pathways involving insulin and testosterone.

The role of testosterone replacement therapy and statin use, and their combination, in prostate cancer.

PURPOSE: Previous studies have reported conflicting results in the associations of testosterone replacement therapy (TTh) and statins use with prostate cancer (PCa). However, the combination of these treatments with PCa stage and grade at diagnosis and prostate cancer-specific mortality (PCSM) and by race/ethnicity remains unclear. METHODS: We identified non-Hispanic White (NHW, N = 58,576), non-Hispanic Black (NHB, n = 9,703) and Hispanic (n = 4,898) men diagnosed with PCa in SEER-Medicare data 2007-2011. Pre-diagnostic prescription of TTh and statins was ascertained for this analysis. Multivariable-adjusted logistic and Cox proportional hazards models were used to evaluate the association of TTh and statins use with PCa stage and grade and PCSM. RESULTS: 22.5% used statins alone, 1.2% used TTh alone, and 0.8% used both. TTh and statins were independently, inversely associated with PCa advanced stage and high grade. TTh plus statins was associated with 44% lower odds of advanced stage PCa (OR 0.56, 95% CI 0.35-0.91). As expected, similar inverse associations were present in NHWs as the overall cohort is mostly comprised NHW men. In Hispanic men, statin use with or without TTh was inversely associated with aggressive PCa. CONCLUSIONS: Pre-diagnostic use of TTh or statins, independent or in combination, was inversely associated with aggressive PCa, including in NHW and Hispanics men, but was not with PCSM. The findings for use of statins with aggressive PCa are consistent with cohort studies. Future prospective studies are needed to explore the independent inverse association of TTh and the combined inverse association of TTh plus statins on fatal PCa.

Endocrinological and ovarian histological investigations in assigned female at birth transgender people undergoing testosterone therapy.

RESEARCH QUESTION: What are the hormonal and ovarian histological effects of a gender affirming hormonal therapy in assigned female at birth (AFAB) transgender people? DESIGN: Prospective observational study of 70 AFAB transgender people taking testosterone therapy before gender-affirming surgery (hystero-oophorectomy). A gynaecological ultrasonographic scan was undertaken and serum hormone concentrations measured, including anti-Müllerian hormone (AMH) and androgenic profile. Histological ovarian evaluation was assessed in both ovaries, including the developmental stages of the follicles. RESULTS: The mean age of the population was 27.7+/-5.14 years. The main biochemical parameters were total testosterone levels 781.5 ± 325.9 ng/dl; AMH levels 3.2 ± 1.4 ng/ml; FSH and LH levels 4.9 ± 2.5 IU/l and 3.9 ± 2.9 IU/l, respectively; and oestradiol values 47.6 ± 13.7 pg/ml. Fifty-five AFAB underwent gynaecological ultrasound before surgery and antral follicles were found in 43 out of 47 ultrasounds (91.5%) (without the presence of a dominant follicle or corpus luteum). Histological follicles were mostly in the primordial stage (88.0) and 3.3% were atretic. The thickness of the tunica albuginea was widely heterogeneous (range 0.15-1.45 mm) and luteinization of the stromal cells was observed in 68.6% of the samples. A negative correlation between testosterone levels and total antral follicles was found (Rs= -0.306, P = 0.029). CONCLUSIONS: AFAB transgender people taking testosterone therapy show cortical follicle distribution in the range previously reported in fertile cisgender women of reproductive age. The follicular population may not be altered as a result of the gender-affirming hormonal therapy, although some cortical and stromal changes have been observed.

Testosterone Therapy and Cardiovascular Risk: A Critical Analysis of Studies Reporting Increased Risk.

BACKGROUND: Treatment of "adult-onset hypogonadism" (AOH) with exogenous testosterone therapy (TTh) to raise serum testosterone (T) levels may influence cardiovascular (CV) risk factors in patients with AOH, whereas low endogenous T levels are associated with an increased CV risk and mortality. AIM: To critically evaluate studies reporting increased CV risk associated with TTh and to provide an overview of the risks and benefits of restoring T levels through exogenous TTh. METHODS: A review of publications focusing on the association between TTh and increased CV risk was conducted, and the study methodologies and conclusions of each were critically evaluated. Further, recent clinical and epidemiological studies associating AOH or TTh with a change in CV risk, and pertinent hematologic and vascular effects noted in animal studies and in vitro, as well as in clinical practice were also reviewed. OUTCOMES: A review of the literature shows that untreated testosterone deficiency and/or low T is associated with an increase in CV risk and adverse outcomes, with numerous studies and meta-analyses to support a positive association between exogenous TTh and an improvement in CV risk factors in men with AOH. RESULTS: Numerous studies in the literature demonstrate the positive benefits of using TTh; however, since 2013, some publications have suggested a link to increased CV risk associated with TTh. A number of these studies retrospectively analyzed insurance claims databases using diagnosis codes, procedures codes, and prescription information. Many reviews published since have pointed out the methodological flaws and debatable conclusions of these studies. CLINICAL IMPLICATIONS: A careful assessment of the patient's current health status and CV risk factors should be weighed against the benefits and possible risks resulting from TTh, and consideration should be given to deferring treatment pending resolution or stabilization of CV disease or risk factors. STRENGTHS & LIMITATIONS: In this review, we provide an in-depth analysis of studies reporting increased CV risk with TTh. Many of the studies were not well-designed, randomized, double-blind, prospective clinical trials but rather post hoc analyses of cohort data. These studies may reflect bias in how treatment and nontreatment decisions are made or reflect conclusions based on widely cited methodological flaws. CONCLUSION: Appropriate patient selection supported by low pre-treatment T levels and monitoring T levels during treatment with the goal of achieving and maintaining physiologic levels all contribute to the safe and effective use of TTh in men with AOH. Khera M, Miner M, Jaffe J, et al. Testosterone Therapy and Cardiovascular Risk: A Critical Analysis of Studies Reporting Increased Risk. J Sex med 2021;18:83-98.

Apocrine ductal carcinoma in situ associated with testosterone therapy in a transgender individual.

We report the first case of apocrine ductal carcinoma in situ (DCIS) in a female-to-male transgender individual on testosterone therapy (TT). The gender confirmation total mastectomy revealed 2 cm DCIS with apocrine cytology, high nuclear grade with associated calcification, and necrosis. Immunohistochemistry revealed the DCIS was negative for ER, positive for AR with HER2/neu overexpression (3+). This patient with negative screening mammography developed apocrine DCIS on TT, suggesting that gender-affirming hormone therapy may have advanced malignant transformation of atypical apocrine cells. This may have implications for increased surveillance within the transgender population.

Obstructive Sleep Apnea Is Associated With Polycythemia in Hypogonadal Men on Testosterone Replacement Therapy.

BACKGROUND: Polycythemia (erythrocytosis) is a known side effect of testosterone (T) replacement therapy (TRT) and appears to correlate with maximum T levels. There is also a well-established association between obstructive sleep apnea (OSA) and the development of polycythemia, which confers additional long-term cardiovascular morbidity. Synergy between TRT and OSA in the development of polycythemia remains poorly understood. AIM: The objective of this study was to retrospectively assess the relationship of OSA and secondary polycythemia in hypogonadal men receiving TRT. METHODS: We performed a retrospective chart review of all men treated by a single provider from 2015 to 2019 for the diagnosis of hypogonadism. Patients who developed a hematocrit of 52% or greater were classified as having polycythemia. OSA was identified via clinical documentation or use of nocturnal continuous positive airway pressure. Demographics, laboratory values, treatment details, and comorbidities were recorded. Data were reported as mean ± SD for parametric variables and median [interquartile range] for non-parametric values. OUTCOME: The primary outcome of this study was the association between OSA and polycythemia in hypogonadal men on TRT. RESULTS: 474 men were included in this study. 62/474 (13.1%) men met the criteria for the diagnosis of polycythemia with a median hematocrit of 53.6 [interquartile range 52.6, 55.5]. Univariate analysis demonstrated a strong positive association between polycythemia and the concomitant diagnosis of OSA in hypogonadal men (P = .002). Even after correcting for age, body mass index (BMI), and peak T levels in the multivariate analysis (P = .01), this relationship remained significant with an odds ratio of 2.09 [95% CI 1.17, 3.76]. 37 men on TRT with polycythemia and OSA were included in the final cohort with a mean age of 59.2 ± 11.4 years, mean BMI of 32.4 ± 6.0, and median time from TRT initiation to polycythemia diagnosis of 3 years. All patients diagnosed with OSA were prescribed continuous positive airway pressure with poor compliance noted in 52.8% of men. 37.8% were managed via phlebotomy and 59.5% were managed via dose de-escalation of TRT. In hypogonadal men on TRT with polycythemia, BMI was the only risk factor strongly associated with OSA (P = .013). CLINICAL TRANSLATION: In hypogonadal men (particularly those with elevated BMI) on TRT who develop secondary polycythemia, a diagnosis of OSA should be strongly considered. STRENGTHS & LIMITATIONS: This is a single provider retrospective study and further studies are needed to assess generalizability. CONCLUSIONS: In this retrospective single-center cohort, the development of polycythemia in hypogonadal men on TRT was associated with an increased prevalence of OSA. Lundy SD, Parekh NV, Shoskes DA. Obstructive Sleep Apnea Is Associated With Polycythemia in Hypogonadal Men on Testosterone Replacement Therapy. J Sex Med 2020;17:1297-1303.

Long-term treatment with testosterone undecanoate injections in men with hypogonadism alleviates erectile dysfunction and reduces risk of major adverse cardiovascular events, prostate cancer, and mortality.

Objective: The association between erectile dysfunction (ED), hypogonadism, cardiovascular disease, and type 2 diabetes is well documented, but long-term data are limited. The aim of this study is to investigate effects of long-term testosterone therapy (TTh) with testosterone undecanoate in men with hypogonadism and ED.Patients and methods: Observational, prospective registry of 805 hypogonadal men with different degrees of ED, evaluated by the International Index of Erectile Function - Erectile Function Domain. Four hundred and twelve patients underwent TTh, 393 patients served as controls, with an observation period up to 12 years.Results: TTh led to substantial and sustained reduction of ED; improvement in erectile function was significant for each successive year until year 9. This was accompanied by improvements in cardiometabolic risk factors and urinary function throughout the 12-year follow-up period. Benefits of TTh were stronger for patients with moderate/severe ED than for patients with no/minor ED. Incidence of prostate cancer, major adverse cardiovascular events, and mortality were significantly lower in men on TTh compared with untreated men.Conclusion: Long-term TTh for up to 12 years alleviates ED, improves cardiometabolic risk factors, and reduces prostate cancer. Patients must stay on TTh consistently for a long time to achieve maximum benefits of TTh.