Breast and cervical cancer in transgender men: literature review and a case report.

Transgender individuals exhibit a higher prevalence of cancer-related risk factors, such as substance abuse and sexually transmitted infections. These factors, coupled with suboptimal adherence to cancer screening recommendations, may lead to a higher incidence of cancers, such as breast and cervical cancer, and contribute to delayed diagnoses in transgender patients. Herein, we report a unique case of a transgender man with a history of alcohol and drug abuse, undergoing gender-affirming exogenous testosterone therapy, who developed synchronous locally advanced breast cancer and human papilloma virus (HPV)-related cervical cancer. He underwent concurrent chemoradiation for cervical cancer and surgery followed by endocrine therapy for breast cancer. The treatments were suboptimals due to patient's comorbidities, among them liver cirrhosis leading to an early death. Additionally, we have conducted a review of existing literature, including case reports, clinical studies, and review articles investigating the role of potential risk factors specifically related to breast and cervical tumors in transgender men. Gender-affirming testosterone therapy is common among transgender men to induce gender affirmation, but its link to breast cancer risk remains ambiguous, with studies being limited and sometimes contradictory. Conversely, HPV is a well-established cause of up to 99% of cervical cancers. Despite persistent risk for cervical cancer in transgender men who retain their cervix, several studies indicate notable disparities in screening adherence, due to personal and structural barriers. Moreover, alcohol and drug use disorders, commonly encountered in transgender population, may negatively influence the adherence to screening programs. Current cancer screening guidelines for this population are somewhat unclear, and specific programs based on more robust data are urgently required along with further tailored studies.

Breast and cervical cancer in transgender men: literature review and a case report Transgender individuals are persons whose gender identity does not conform to that typically associated with the sex to which they were assigned at birth. Transgender people may have more cancer-related risk factors, such as substance abuse and sexually transmitted infections. These factors, along with suboptimal adherence to cancer screening, may lead to a higher incidence of cancers, among them breast and cervical cancer, and may also contribute to delayed diagnoses. Herein we report the case of a transgender man, recorded as female at birth but identifying as male, with a history of alcohol and drug abuse. He underwent testosterone therapy in order to affirm his gender. Moreover, he refused cancer screening, due to personal and social barriers. During the transition, he developed simultaneously a locally advanced breast cancer and a cervical cancer, the latter related to an infection from Human Papillomavirus. The patient was treated with chemoradiation for cervical cancer, and with surgery followed by endocrine therapy for breast cancer. The treatments were suboptimals due to patient's comorbidities, partly related to his previous lifestyle. Additionally, we have conducted a review of existing literature on the topic. Trangender men usually undergo testosterone to induce gender-affirmation. The role of testosterone therapy in breast cancer development remains unclear, with studies being contradictory. Conversely, Human Papillomavirus is a well-established cause of cervical cancers. Transgender men who retain their cervix are at risk for cervical cancer. Despite the persistent risk, notable disparities in screening adherence, due to personal and structural barriers, are reported. Moreover, alcohol and drug use disorders, commonly encountered in transgender population, may contrtibute to the low adherence to screening programs. Furthermore, screening guidelines are somewhat unclear, and specific programs are urgently required.

Endometriosis in Transgender Men: Bridging Gaps in Research and Care-A Narrative Review.

Endometriosis is a debilitating gynecological condition commonly seen in individuals designated female at birth; however, there has been limited research focused on its prevalence and impact among transgender men. This narrative review aims to fill a critical knowledge gap by exploring the epidemiology, clinical manifestations, management strategies, and quality-of-life implications of endometriosis among transgender individuals who identify as male. Specifically, this study seeks to estimate the prevalence rates and describe the symptoms experienced by transgender men undergoing testosterone therapy. Additionally, it addresses the diagnostic challenges posed by hormonal treatments and the lack of culturally competent healthcare services for this population. Recent molecular studies indicate that hormonal imbalances, such as increased estrogen synthesis and progesterone resistance, are significant factors in the persistence of endometriosis symptoms despite testosterone therapy. Moreover, evidence suggests that testosterone therapy may not always suppress endometrial activity completely, contributing to the persistence of symptoms in some individuals. Endometriosis in transgender men requires personalized approaches that consider both testosterone therapy and its interactions with endometriosis, as well as fertility preservation and the psychosocial aspects of treatment. This review emphasizes the necessity of taking an inclusive approach in both research and clinical practice to improve healthcare outcomes for this underserved population. The results demonstrate how continued research, education, and healthcare services tailored specifically to transgender men are necessary to better understand and treat endometriosis, thus improving both their overall health and quality of life.

Battle of the Blocks: Which Pain Management Technique Triumphs in Gender-Affirming Bilateral Mastectomies?

Background: Gender-affirming mastectomy, performed on transgender men and non-binary individuals, frequently leads to considerable postoperative pain. This pain can significantly affect both patient satisfaction and the overall recovery process. The study examines the efficacy of four analgesic techniques pectoral nerve (PECS) 2 block, erector spinae plane (ESP) block, thoracic wall local anesthesia infiltration (TWI), and systemic multimodal analgesia (SMA) in managing perioperative pain, with special consideration for the effects of chronic testosterone therapy on pain thresholds. Methods: A retrospective analysis was conducted on patients aged 18 - 45 who underwent gender-affirming bilateral mastectomies at a New York City community hospital. The study compared intraoperative and post-anesthesia care unit (PACU) opioid consumption, postoperative pain scores, the interval to first rescue analgesia, and total PACU duration among the four analgesic techniques. Results: The study found significant differences in intraoperative and PACU opioid consumption across the groups, with the PECS 2 block group showing the least opioid requirement. The PACU morphine milligram equivalent (MME) consumption was highest in the SMA group. Postoperative pain scores were significantly lower in the PECS and ESP groups at earlier time points post-surgery. However, by postoperative day 2, pain scores did not significantly differ among the groups. Chronic testosterone therapy did not significantly impact intraoperative opioid requirements. Conclusion: The PECS 2 block is superior in reducing overall opioid consumption and providing effective postoperative pain control in gender-affirming mastectomies. The study underscores the importance of tailoring pain management strategies to the unique physiological responses of the transgender and non-binary community. Future research should focus on prospective designs, standardized block techniques, and the complex relationship between hormonal therapy and pain perception.

Microphallus early management in infancy saves adulthood sensual life: A comprehensive review.

Microphallus/Micropenis is a rare condition with significant physical and psychological implications for affected individuals. This article comprehensively reviews micropenis, its etiology, epidemiology, and various treatment options. We conducted a thorough literature review to collect relevant information on micropenis and microphallus, as well as related disorders. Our primary databases were PubMed, Medline, and Google Scholar. We searched for articles published in English between 2000 and 2023. Our analysis included 67 review articles, 56 research studies, 11 case reports, one guideline, and one editorial. Our search terms included "microphallus", "micropenis", "congenital hypogonadotropic hypogonadism", "androgen insensitivity syndrome", "pediatric management of micropenis", "testosterone therapy", and "psychosocial implications of micropenis". We focused on diagnosing micropenis and related conditions, including hormonal assessments, medical and surgical treatment options, psychosocial and psychological well-being, sexual development of adolescents, and sociocultural influences on men's perceptions of penile size. Additionally, we explored parenting and family dynamics in cases of micropenis and disorders of sex development, implications of hormonal treatment in neonates, and studies related to penile augmentation procedures and their effectiveness. The article highlights the importance of early diagnosis and intervention in addressing the physical and psychological well-being of individuals with micropenis. Surgical procedures, such as penile lengthening and girth enhancement, and non-surgical approaches like hormonal therapy are explored. The significance of psychological support, education, and lifestyle modifications is emphasized. Early management and comprehensive care are crucial for individuals with micropenis, from infancy to adolescence and beyond. A multidisciplinary approach involving urologists, endocrinologists, and mental health professionals is recommended. Regular assessment of treatment effectiveness and the need for updated guidelines are essential to provide the best possible care. Healthcare professionals should prioritize early diagnosis, and neonatologists should measure stretched penile length in neonates. A collaborative effort is needed among professionals, parents, and affected individuals to create a supportive environment that recognizes worth beyond physical differences. Continuous research and evidence-based updates are crucial for improving care standards.

Testosterone therapy for functional hypogonadism in middle-aged and elderly males: current evidence and future perspectives.

Population aging is a global phenomenon driving research focus toward preventing and managing age-related disorders. Functional hypogonadism (FH) has been defined as the combination of low testosterone levels, typically serum total testosterone below 300-350 ng/dL, together with manifestations of hypogonadism, in the absence of an intrinsic pathology of the hypothalamic-pituitary-testicular (HPT) axis. It is usually seen in middle-aged or elderly males as a product of aging and multimorbidity. This age-related decline in testosterone levels has been associated with numerous adverse outcomes. Testosterone therapy (TTh) is the mainstay of treatment for organic hypogonadism with an identifiable intrinsic pathology of the HPT axis. Current guidelines generally make weak recommendations for TTh in patients with FH, mostly in the presence of sexual dysfunction. Concerns about long-term safety have historically limited TTh use in middle-aged and elderly males with FH. However, recent randomized controlled trials and meta-analyses have demonstrated safe long-term outcomes regarding prostatic and cardiovascular health, together with decreases in all-cause mortality and improvements in various domains, including sexual function, body composition, physical strength, bone density, and hematopoiesis. Furthermore, there are numerous insightful studies suggesting additional benefits of TTh, for instance in cardio-renal-metabolic conditions. Specifically, future trials should investigate the role of TTh in improving symptoms and prognosis in various clinical contexts, including sarcopenia, frailty, dyslipidemia, arterial hypertension, diabetes mellitus, fracture risk, heart failure, stable angina, chronic kidney disease, mood disorders, and cognitive dysfunction.

Testosterone therapy in older men: clinical implications of recent landmark trials.

Testosterone therapy for men with hypogonadism due to identifiable hypothalamic-pituitary-testicular (HPT) pathology is uncontroversial. However, the risks and benefits of testosterone for men with clinical features of hypogonadism in the absence of identifiable HPT axis pathology have been uncertain. Recent landmark placebo-controlled trials assessed the benefits and risks of testosterone therapy (≤3 years) for middle-aged and older men with symptoms and possible signs of hypogonadism or end-organ androgen deficiency, low or low-normal serum testosterone concentrations, but no HPT pathology: Testosterone therapy (1) had modest-but clinically significant-benefits on average self-reported energy and mood, sexual function, and satisfaction; (2) in conjunction with a lifestyle programme, reversed or reduced incident type 2 diabetes mellitus (T2D) in men at high risk of or newly diagnosed with T2D; (3) modestly improved objectively assessed muscle strength and timed walking distance; (4) increased bone density and strength, but did not reduce falls or typical osteoporotic fractures and surprisingly increased the risk of fractures typically attributable to trauma; and (5) did not significantly increase the risk of myocardial infarction, stroke, or prostate cancer. These landmark trials help to inform clinical decision-making about testosterone therapy for men.

Beneficial effects of exercise, testosterone, vitamin D, calcium and protein in older men-A randomized clinical trial.

BACKGROUND: Due to increasing older populations worldwide, injuries, disabilities and deaths caused by falls among the elderly represent a growing human and societal problem. We aimed to improve health among men of at least 70 years of age with low-normal to low testosterone and mobility problems by using testosterone undecanoate (TU) injections, progressive strength training, and oral supplements of vitamin D, calcium and protein. METHODS: This was a single-centre, randomized, placebo-controlled, double-blind trial with 148 older men with a median age of 77 (73-81) years, testosterone levels at median 8 (5-9) nmol/L (full range from 1.1 to 12.9 nmol/L) and mobility problems, recruited at University Hospital of Copenhagen, Herlev Hospital, Denmark. Participants were randomized into four arms for 20 weeks: (1) TU therapy (n = 37); (2) progressive resistance training with supplements of calcium, vitamin D and protein (n = 36); (3) both interventions combined (n = 36); or (4) no intervention (n = 39). The main outcome measure was the 30-s chair stand test, due to test performance correlating with the risk of serious fall injuries and lower extremity muscle strength. Outcome measurements were performed at baseline and after 20 weeks. RESULTS: After the intervention, the combination group receiving progressive resistance training, TU and supplements achieved a median score of 13 (11-15) compared to the control group at 10 (0-14) in the 30-s chair stand test (P = 0.003). This median improvement of 3.0 was clinically important. Compared to the control group, participants in the combination group also increased quality of life (P < 0.05) and reduced both tiredness (P < 0.05) and leg fat (P < 0.05) and had higher variability in the RR interval (P < 0.01). The group receiving TU reduced gynoid and leg fat compared to the control group (both P < 0.05). Blood tests improved for several variables, especially in the combination group. There was no statistically significant increase in adverse effects from either the supplements or training. CONCLUSIONS: In men ≥70 years old with low-normal to low testosterone and mobility problems, supplements of testosterone, calcium, vitamin D and protein combined with progressive resistance training improved 30-s chair stand test performance, muscle strength and quality of life. Both tiredness and leg fat were reduced, and RR interval variability was increased. Significant adverse effects were not observed.

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 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.

Voice and Communication in Transmasculine Individuals One Year Under Testosterone Therapy: A Qualitative Study.

OBJECTIVES/HYPOTHESES: The purpose of this study was to investigate voice and communication difficulties in transmasculine individuals to develop evidence-based voice and communication training programs. STUDY DESIGN: Qualitative study. METHODS: Eight transmasculine individuals, who had received testosterone therapy (TT) for at least 1year, were included in this study. Semistructured interviews were conducted by two experienced voice clinicians. The software program NVivo was used for transcribing and coding the interviews. Data were processed using a thematic analysis. RESULTS: The thematic analysis resulted in the identification of five major themes. Most transmasculine individuals experienced a pitch decrease during the first year of TT and encountered voice-related problems, with a higher incidence during the initial period. Additionally, some participants experienced increased satisfaction with how others attributed their gender after 1year of TT. However, others still experienced a discrepancy between external gender attribution, self-attribution, and their desired attribution by others. Many participants did not receive voice and communication training. In many cases, voice had a significant impact on their well-being and daily life. CONCLUSIONS: It's difficult to generalize the results of the current study, since the population of transmasculine individuals is heterogeneous in terms of their subjective gender positioning, desired gender attribution, gender attribution received from others, and gender-related aspects of their vocal situation. Some clients may express dissatisfaction with specific aspects of their voice and communication and may require professional support. Therefore, clinical practice for transmasculine individuals should adopt an individualized approach based on a comprehensive examination of the client's perspective.

Association between testosterone replacement therapy and cardiovascular outcomes: A meta-analysis of 30 randomized controlled trials.

BACKGROUND: The Cardiovascular safety of testosterone replacement therapy (TRT) among men with hypogonadism is not well established to date. Hence, we sought to evaluate the cardiovascular disease (CVD) outcomes among patients receiving testosterone therapy by using all recently published randomized controlled trials. METHODS: We performed a systematic literature search on PubMed, EMBASE, and Clinicaltrial.gov for relevant randomized controlled trials (RCTs) from inception until September 30th, 2023. RESULTS: A total of 30 randomized trials with 11,502 patients were included in the final analysis. The mean age was ranging from 61.61 to 61.82 years. Pooled analysis of primary and secondary outcomes showed that the incidence of any CVD events (OR, 1.12 (95%CI: 0.77-1.62), P = 0.55), stroke (OR, 1.01 (95%CI: 0.68-1.51), P = 0.94), myocardial infarction (OR, 1.05 (95%CI: 0.76-1.45), P = 0.77), all-cause mortality (OR, 0.94 (95%CI: 0.76-1.17), P = 0.57), and CVD mortality (OR, 0.87 (95%CI: 0.65-1.15), P = 0.31) was comparable between TRT and placebo groups. CONCLUSION: Our analysis indicates that for patients with hypogonadism, testosterone replacement therapy does not increase the CVD risk and all-cause mortality.

TRACK_9: Testosterone replacement assessment: Classical vs. functional hypogonadism­knowledge from a 9­year study

BACKGROUND AND OBJECTIVE: The longitudinal efficacy and clinical utility of Testosterone Therapy (TTh) in ameliorating functional hypogonadism (FH) remain contentious, with long-term data being scarce. To address this lacuna, a comprehensive long-term registry study, stratifying patients across a spectrum of hypogonadal etiologies, offers a robust investigative paradigm. MATERIALS AND METHODS: This 9-year registry, encompassing 650 patients (equivalent to 4,362 cumulative years of treatment), included 188 patients diagnosed with FH (mean age 42.3 ± 11.3 years) and 462 individuals with classical hypogonadism (CH). The cohort segregated into 266 men with primary hypogonadism (PH, mean age 34.0 ± 11.7 years) and 196 with secondary hypogonadism (SH, mean age 31.9 ± 12.0 years). Uniform treatment across the cohort involved intramuscular administration of testosterone undecanoate (1,000 mg). A comparative analysis was conducted focusing on anthropometric, metabolic, and safety parameters. RESULTS: Serum testosterone levels increased from 6.6 ± 2.4 to 19.3 ± 2.9 nmol/L (p < 0.001). TTh was linked with weight reduction and decreased waist circumference (WC) in both CH and FH cohorts (both p < 0.001). Cox regression and Kaplan-Meier analyses delineated disparities: men with FH demonstrated a higher propensity for losing > 10% body weight and > 5% WC compared to CH (hazard ratio [HR] 1.3 [1.1-1.4], p = 0.008 and HR 1.4 [1.3-1.5], p = 0.001). Increases in hematocrit > 50% were uniform across groups, albeit amelioration of anemia was more pronounced in FH versus CH (p = 0.002). Increments of prostate-specific antigen (PSA) levels were more likely to occur in FH (HR 1.3 [1.1-1.6], p = 0.003). FH patients exhibited pronounced improvements in metabolic parameters and in aging male symptom score (AMS) and IIEF-EF questionnaire scores. These effects were markedly modulated by age and initial weight. Subgroup analysis of age-matched obese patients revealed an accentuated impact of TTh in CH compared to FH. DISCUSSION AND CONCLUSION: The therapeutic outcomes of TTh across distinct hypogonadal populations demonstrate heterogeneous responses, significantly influenced by diagnostic categorization, age, and baseline risk factor profiles.

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.

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.

Testosterone therapy and the risk of cardiovascular disease in older, hypogonadal men.

The debate over the cardiovascular (CV) implications of testosterone therapy (TT) have resulted in diverging safety recommendations and clinical guidelines worldwide. This narrative review synthesizes and critically evaluates long-term studies examining the effects of TT within the context of aging, obesity, and endogenous sex hormones on CV disease (CVD) risk to support informed clinical decision-making. Observational studies have variably linked low endogenous testosterone with increased CVD risk, while randomized controlled trials (RCTs) demonstrate that TT yields cardiometabolic benefits without increasing short-term CV risk. The TRAVERSE trial, as the first RCT powered to assess CVD events, did not show increased major adverse cardiac events (MACE) incidence; however, its limitations - specifically the maintenance of testosterone at low-normal levels, a high participant discontinuation rate, and short follow-up - warrant a careful interpretation of its results. Furthermore, findings from the TTrials cardiovascular sub-study, which showed an increase in non-calcified plaque, indicate the need for ongoing research into the long-term CV impact of TT. The decision to initiate TT should consider the current evidence gaps, particularly for older men with known CVD. The CV effects of maintaining physiological testosterone levels through exogenous means remain to be fully explored. Until more definitive evidence is available, clinical practice should prioritize individualized care and informed discussions on the potential CV implications of TT.

Testosterone replacement therapy: association with mortality in high-risk patient subgroups.

OBJECTIVES: We describe studies determining the association between testosterone therapy (TTh) and mortality. MATERIALS & METHODS: We used a registry database of 737 men with adult-onset testosterone deficiency defined as presenting with low serum total testosterone (TT) levels ≤12.1 nmol/L and associated symptoms over a near 10-year follow-up. We compared associations between testosterone undecanoate (TU), cardio-metabolic risk factors and mortality using non-parametric statistics followed by separate Cox regression models to determine if any association between TU and morality was independent of age and cardio-metabolic risk factors. Finally, the association between TU and mortality was studied in men stratified by cardio-metabolic risk. RESULTS: During a median follow-up interquartile range (IQR) of 114 (84-132) months, 94 of the 737 men died. TU (ref: non-treatment) was associated with mortality; hazard ratio = 0.23, 95% confidence intervals = 0.14-0.40. Cox's regression models showed the above association to be independent of baseline age, waist circumference, hemoglobin A1c, lipids, blood pressure, smoking, and type 2 diabetes. These variables remained associated with mortality. We finally stratified the men by the high-risk baseline variables and established that the association between mortality and TU was only evident in men at higher risk. A possible explanation could lie with the "law of initial value," where greater improvements are evident following treatment in patients with worse baseline values. CONCLUSIONS: This study with long follow-up confirms that TTh is associated with lower mortality in men with adult-onset TD. This association was evident only in men with greater cardio-metabolic risk factors who demonstrated greater benefit.

Clinical evaluation and treatment in men with low testosterone levels and prostate cancer.

INTRODUCTION: A high prevalence of low testosterone levels has been reported in men with prostate cancer. The use of testosterone therapy in men with a history of prostate cancer is still controversial, and there is uncertainty regarding the management of these patients. METHODS: We analyzed the European and American guidelines on this topic and presented the clinical experience in the management of patients with low testosterone levels and a history of prostate cancer in one of the world's leading cancer centers. RESULTS: According to the published evidence to date, testosterone therapy in men with prostate cancer does not increase the risk of prostate cancer recurrence in the short and medium term, but there is a lack of data on the long term. Symptomatic men with low testosterone levels who are candidates for this therapy need a thorough clinical evaluation before commencing testosterone therapy. Evaluation of prostate cancer history including type of treatment administered, pathologic stage of prostate cancer and prostate specific antigen should be requested before and during testosterone treatment to assess its trend. CONCLUSION: Prostate-specific antigen should remain undetectable after radical prostatectomy or stable after radiotherapy. Otherwise, it would be a sign of uncontrolled prostate cancer, and the patient may require cessation of testosterone therapy and referral to oncology for further evaluation.

Hepcidin Reduction during Testosterone Therapy in Men with Type 2 Diabetes: A Randomized, Double-Blinded, Placebo-Controlled Study.

High hepcidin is linked to low-grade inflammation and lower iron levels. The consequences of testosterone replacement therapy (TRT) on inflammation and the risk of cardiovascular disease (CVD) are undetermined. We investigate the effect of TRT on the inflammatory cardiovascular risk markers hepcidin-iron, fibroblast growth factor 23 (FGF23)-phosphate-klotho, and calprotectin pathways. METHODS: A randomized, placebo-controlled, double-blinded study at an academic tertiary-care medical center. Interventions were testosterone gel (TRT, n = 20) or placebo gel (n = 19) for 24 weeks. We included 39 men (50-70 years) with type 2 diabetes (T2D) on metformin monotherapy with bioavailable testosterone levels <7.3 nmol/L. Body composition was assessed with DXA- and MRI-scans; the main study outcomes were serum hepcidin-iron, FGF23, phosphate, klotho, and calprotectin. RESULTS: Hepcidin levels decreased during TRT (ß = -9.5 ng/mL, p < 0.001), lean body mass (ß = 1.9 kg, p = 0.001) increased, and total fat mass (ß = -1.3 kg, p = 0.009) decreased compared to placebo. Delta hepcidin was not associated with changes in lean body mass or fat mass. Iron and the pathways of FGF23-phosphate-klotho and calprotectin were unchanged during TRT. CONCLUSIONS: During TRT, the reduction in hepcidin was not associated with circulating iron levels, lean body mass, or fat mass; these findings suggested a direct anti-inflammatory effect of TRT and no indirect effect mediated through these factors.

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.