Recognizing the True Value of Testosterone Therapy in Health Care.

The Impact of Testosterone Therapy in Men on Cardiovascular Risk: Don’t Be Too Quick to Condemn

Research in brief

The use of exogenous testosterone to treat hypogonadism in the men with a history of prostate cancer (CaP) remains controversial due to fears of cancer recurrence or progression. Due to the detrimental impact of hypogonadism on patient quality of life, recent work has examined the safety of testosterone therapy (TTh) in men with a history of CaP. In this review, we evaluate the literature with regards to the safety of TTh in men with a history of CaP. TTh results in improvements in quality of life with little evidence of biochemical recurrence or progression in men with a history of CaP, or de novo cancer in unaffected men. An insufficient amount of evidence is currently available to truly demonstrate the safe use of TTh in men with low risk CaP. In men with high-risk cancer, more limited data suggest that TTh may be safe, but these findings remain inconclusive. Despite the historic avoidance of TTh in men with a history of CaP, the existing body of evidence largely supports the safe and effective use of testosterone in these men, although additional study is needed before unequivocal safety can be demonstrated.

Up to 40% of men with type 2 diabetes (T2DM) and metabolic syndrome (MetS) have hypogonadotrophic hypogonadism (HH). Men with HH are at increased risk of cardiovascular (CV) and all-cause mortality, as well as of the development of incident T2DM. To review the current literature on the metabolic effects of testosterone therapy (TTh) in men with T2DM and MetS. We searched MEDLINE, Embase, and Cochrane Reviews for articles on T2DM, HH, testosterone deficiency, and CV and all-cause mortality published between May 2005 and July 2018, yielding 1817 articles, including 54 clinical trials and 32 randomized controlled trials (RCTs). The main outcomes were glycemic control, insulin resistance, lipid profile, and metabolic markers associated with increased CV risk. RCTs of TTh suggest significant benefits for sexual function, quality of life, glycemic control, insulin sensitivity, anemia, bone density, and fat and lean muscle mass that might be expected to translate into reduced long-term morbidity and mortality. Several longitudinal and observational studies suggest long-term sustained improvements in metabolic parameters and a trend toward reduced CV and all-cause mortality, especially in men at increased CV risk, such as those with T2DM and MetS. The greatest benefit is seen in those men treated with TTh to target levels and for longer durations. Meta-analyses of RCTs, rather than providing clarification, may have further confused the issue by including underpowered studies of inadequate duration, multiple therapy regimens, some obsolete or withdrawn, and built-in bias in terms of studies included or excluded from analysis. Hackett G. Metabolic Effects of Testosterone Therapy in Men with Type 2 Diabetes and Metabolic Syndrome. Sex Med Rev 2019;7:476-490.

Background: Late-onset hypogonadism (LOH) presents with low serum testosterone (TT) levels and sexual and nonsexual symptoms. Erectile dysfunction affects a man’s self-esteem and as a result partner relationship and quality of life.Objectives: To investigate the andrological clinical profile outcomes of testosterone therapy (TTh) in men (n = 88) with symptomatic LOH complaints and symptoms.Main outcome measures: Erectile function was assessed using the International Index of Erectile Function-5 questionnaire at baseline and at 6 and 12 months of TTh. In addition, penile length was measured at baseline and 12 months. We also evaluated nocturnal penile tumescence (NPT, using RigiScan) and blood flow of cavernous arteries (penile Doppler ultrasonography) at baseline and 12 months of TT.Materials and methods: Eighty-eight LOH men (Mage 51.1 years) with erectile dysfunction, all with serum TT <10.4 nmol/L before TTh. Patients received intramuscular long-acting testosterone undecanoate for 12 months.Results: Following TTh, in all patients, serum TT levels were restored within 3 months to normal levels. Compared with baseline values, erectile function significantly improved at 6 (mean score increase 1.95) and 12 months (mean score increase 2.16). No significant changes in penile length were observed. NPT significantly improved at 12 months in terms of both the frequency (mean increase 1.27 times) and duration of rigidity (mean increase 5.12 min). As regards the blood flow of the cavernous arteries, we observed a significant improvement (decrease of 1.16 cm/s) and end diastolic velocity of the penile arteries.Conclusion: TTh in men with LOH resulted in improvement of the erectile function, NPT, and to some extent the blood flow of the cavernous arteries.

Purpose of reviewThe purpose of this article is to examine the contemporary data linking testosterone therapy in overweight and obese men with testosterone deficiency to increased lean body mass, decreased fat mass, improvement in overall body composition and sustained weight loss. This is of paramount importance because testosterone therapy in obese men with testosterone deficiency represents a novel and a timely therapeutic strategy for managing obesity in men with testosterone deficiency.Recent findingsLong-term testosterone therapy in men with testosterone deficiency produces significant and sustained weight loss, marked reduction in waist circumference and BMI and improvement in body composition. Further, testosterone therapy ameliorates components of the metabolic syndrome. The aforementioned improvements are attributed to improved mitochondrial function, increased energy utilization, increased motivation and vigor resulting in improved cardio-metabolic function and enhanced physical activity.SummaryThe implication of testosterone therapy in management of obesity in men with testosterone deficiency is of paramount clinical significance, as it produces sustained weight loss without recidivism. On the contrary, alternative therapeutic approaches other than bariatric surgery failed to produce significant and sustained outcome and exhibit a high rate of recidivism. These findings represent strong foundations for testosterone therapy in obese men with testosterone deficiency and should spur clinical research for better understanding of usefulness of testosterone therapy in treatment of underlying pathophysiological conditions of obesity.

ABSTRACTIntroduction: The use of testosterone therapy (TTh) in men with prostate cancer (PCa) is relatively new, and controversial, due to the longstanding maxim that TTh is contraindicated in men with PCa. Scientific advances have prompted a reevaluation of the potential role for TTh in men with PCa, particularly as TTh has been shown to provide important symptomatic and general health benefits to men with testosterone deficiency (TD), including many men with PCa who may expect to live 30–50 years after diagnosis.Areas covered: This review outlines the historical underpinnings of the historical belief that TTh ‘fuels’ PCa and the experimental and clinical studies that have radically altered this view, including description of the saturation model. The authors review studies of TTh in men with PCa following radical prostatectomy and radiation therapy, in men on active surveillance, and in men with advanced or metastatic PCa.Expert opinion: TTh provides important symptomatic and overall health benefits for men with PCa who have TD. Although more safety studies are needed, TTh is a reasonable therapeutic option for men with low-risk PCa after surgery or radiation. Data in men on active surveillance are limited, but initial reports are reassuring.

While the cardiovascular safety of testosterone therapy in men remains controversial, limited data exist for trans men treated with testosterone. We assessed cardiovascular events, mortality, and suicide attempts under testosterone therapy in both cis men with hypogonadism and trans men. Participants were recruited from the TriNetX Research network. We compared 117 908 cis men with hypogonadism treated with testosterone with 1:1 propensity score matched cis men not treated. We compared 6251 trans men treated with 6251 trans men not treated with testosterone and 6986 trans men treated to 6986 cis men not treated with testosterone. After 5 years of follow-up, cis men with testosterone therapy had a lower risk of myocardial infarction (HR [hazard ratio]: 0.94, 95% confidence interval [CI] [0.89-0.99], P = .01) with no difference for stroke or mortality, but higher risks of atrial fibrillation (1.27 [1.22-1.32], P < .0001) and acute pulmonary embolism/deep vein thrombosis (1.26 [1.18-1.34], P < .0001). Trans men treated with testosterone had no significant increase in the rate of cardiovascular outcomes as compared to both untreated trans and cis men. There was a lower rate of suicide attempts for trans men treated with testosterone as compared to untreated trans men (0.52 [0.35-0.78], P = .001), without significant differences when compared to untreated cis men. Testosterone treatment in cis men with hypogonadism was associated with a lower risk of myocardial infarction but a higher risk of atrial fibrillation and venous thromboembolism. Testosterone therapy in trans men was not associated with an increased risk of cardiovascular events when compared to untreated trans men or cis men.

The benefits of testosterone therapy (TTh) in the hypogonadal male can be dramatic. Historically, TTh has been contraindicated in prostate cancer (PCa). Current evidence has redefined our understanding of the influence serum testosterone has on prostatic androgen activity. Increasing numbers of hypogonadal men with coexisting PCa emphasizes the importance of describing those who may safely receive TTh. This review aims to present literature that evaluates the efficacy and safety of TTh in men with coexisting PCa. Our study, a comprehensive review of published literature regarding TTh in men with a history of PCa, consisted of studies conducted from the 1940s to 2022. Our review discusses evidence in accordance with previous studies that TTh has a role in patients with localized PCa as it has not been reported to increase rates of recurrence or progression of PCa. The use of TTh in hypongonadal men with a localized PCa has been shown to have positive clinical outcomes without increasing the rate of disease progression or recurrence. Further research, in a randomized controlled setting, is warranted.

The use of testosterone in men with a history of prostate cancer remains controversial in light of established findings linking androgens to prostate cancer growth. However, hypogonadism significantly affects quality of life and has negative sequelae, and the risks and benefits of testosterone therapy might be worthwhile to consider in all men, even those with a history of high-risk prostate cancer. To discuss the effects of testosterone on the prostate and the use of testosterone therapy in hypogonadal men with a history of prostate cancer. Review of the literature examining the effects of testosterone on the prostate and the efficacy and safety of exogenous testosterone in men with a history of prostate cancer. Summary of effects of exogenous and endogenous testosterone on prostate tissue invitro and invivo, with a focus on effects in men with a history of prostate cancer. Testosterone therapy ameliorates the symptoms of hypogonadism, decreases the risk for its negative sequelae, and can significantly improve quality of life. Recent studies do not support an increased risk for de novo prostate cancer, progression of the disease, or biochemical recurrence in hypogonadal men with a history of non-high-risk prostate cancer treated with testosterone therapy. Evidence supporting the use of testosterone in the setting of high-risk prostate cancer is less clear. Despite the historical reluctance toward the use of testosterone therapy in men with a history of prostate cancer, modern evidence suggests that testosterone replacement is a safe and effective treatment option for hypogonadal men with non-high-risk prostate cancer. Additional work to definitively demonstrate the efficacy and safety of testosterone therapy in men with prostate cancer is needed, and persistent vigilance and surveillance of treated men remains necessary.

MP36-09 URINARY FUNCTION AND PROSTATE SAFETY OF LONG-TERM TESTOSTERONE THERAPY (TTh) IN MEN WITH FUNCTIONAL HYPOGONADISM IN A UROLOGICAL REGISTRY STUDY

Testosterone Therapy after Radiation Therapy for Low, Intermediate and High Risk Prostate Cancer

Purpose: To investigate prostate-specific antigen (PSA) and clinical responses to a variety of treatment strategies involving testosterone therapy (TTh) in men with metastatic prostate cancer (mPCa). Materials and Methods: Case records were reviewed for three men with advanced PCa treated with TTh for improved quality of life. Two had bone metastases and nephrostomies at baseline. The third had biochemical recurrence, and continued TTh after developing bone metastases. All rejected androgen deprivation therapy, desired improved quality of life with TTh, and accepted the risk of rapid PCa progression and death. Results: All men experienced substantial symptomatic and health benefits during TTh, including improved strength, vigor, and sexuality. Two reversed substantial weight loss. A 94-year-old man with baseline PSA of 546 ng/mL survived 11 months with continuous TTh, with last PSA of 2493 ng/mL. Two men in their 60s received some form of TTh for 3.5 and 8 years, respectively, and are still alive. None experienced sudden major adverse events. Continuous TTh resulted in progressive rise in PSA to high values. The combination of TTh and enzalutamide provided moderate protection against weakness and fatigue with PSA <10ng/mL for 6 months. PSA values fluctuated from <1.0 to >100 ng/mL within 1–2 months depending on recent androgen status. The most promising strategy appears to be a modified bipolar androgen therapy consisting of repeating cycles of 8 weeks of high-dose TTh followed by 4 weeks of enzalutamide, allowing for prolonged periods of vigor while maintaining PSA control. Conclusions: These pilot results support explorations of new hormonal strategies involving TTh for men with mPCa.

The negative effects of testosterone deficiency (TD) on human health and quality of life are well demonstrated, including signs, symptoms, metabolic syndrome, obesity, and increased mortality. Recently, substantial evidence emerged, demonstrating the benefits of testosterone therapy in men with classical and “age-related” hypogonadism. The US Food and Drug Administration (FDA) opposes testosterone therapy in men with age-related hypogonadism but not in men with classical hypogonadism. The FDA acknowledges that TD merits treatment, but the FDA made an artificial distinction between diagnoses where T treatment is warranted and others where the underlying diagnosis is unknown, and treatment is unwarranted. The FDA labeled the unknown category as “age-related.” Since the FDA is unable to demonstrate that one group differs in benefits or risks from the other, there are no bases for this distinction. This action by the FDA is not based on scientific or clinical evidence. There is no evidence that the response to testosterone therapy of “age-related” hypogonadism occurs via different physiological or biochemical mechanisms than those historically recognized conditions. Also, there is no evidence that “age-related” hypogonadism responds less well to testosterone therapy than “classical” hypogonadism. More importantly, there is no scientific or clinical evidence to suggest that the risks of testosterone therapy in men with “age-related” hypogonadism are worse or different for men with “classical” hypogonadism. For these reasons, we disagree with the FDA position on testosterone therapy in age-related hypogonadism.

Introduction Despite accumulating contrary evidence, adverse urological events of testosterone therapy (TTh) in men with functional hypogonadism remain a concern for many physicians and need to be monitored during TTh. Objective To assess incident adverse urological events in men with functional hypogonadism receiving TTh in comparison to an untreated control group. Methods In a long-term registry study in men with hypogonadism (defined by total testosterone ≤350 ng/mL and at least moderate symptoms assessed by the Aging Males’ Symptoms scale, AMS) in a single urology office, 824 men had functional hypogonadism. 409 men received testosterone undecanoate (TU) injections 1000 mg/12 weeks following an initial 6-week interval (T-group), 415 opted against TTh and served as controls (CTRL). Means and standard deviations of absolute measures over 16 years of treatment and changes over time between groups, compared by mixed effects model for repeated measures with random effect for intercept and fixed effects for time, group and their interaction, and adjusted for age, weight, WC, fasting glucose, blood pressure, lipids and quality of life to account for baseline differences between the two groups are reported. Results Baseline age was 57.7 ± 7.0 years in the T-group and 62.7 ± 5.3 years in CTRL (p &amp;lt; 0.0001). Mean (median) follow-up was 11.9 ± 3.7 (12) years in the T-group and 11.9 ± 3.5 (13) in CTRL. Mean prostate volume (mL) remained stable from 32.1 ± 9.1 to 31.6 ± 9.9 after 16 years in the T-group and from 35.6 ± 6.7 to 36.7 ± 5.9 in CTRL. The estimated adjusted difference between groups was statistically non-significant. Mean PSA (ng/mL) remained stable from 2.1 ± 1.0 to 1.9 ± 0.9 after 16 years in the T-group and increased from 2.5 ± 1.4 to 3.5 ± 1.2 in CTRL (p &amp;lt; 0.0001). The estimated adjusted difference between groups was -1.6 (95% CI: -2.2;-1.1) (p &amp;lt; 0.0001). In the T-group, 13 patients (3.2%) were diagnosed with PCa. Every single PCa diagnosis was made within 18 months from the day of the first testosterone injection to the day of the biopsy resulting in PCa diagnosis. In CTRL, 62 (14.9%) patients were diagnosed with PCa (p &amp;lt; 0.0001 between groups). Among the patients diagnosed with PCa, there was no biochemical recurrence in the T-group where all men were treated by radical prostatectomy. In CTRL, 25 men (6.0%) had one biochemical recurrence of PCa (p &amp;lt; 0.0001 between groups). Among patients in CTRL with a biochemical recurrence, 3 men (0.7%) had a second biochemical recurrence. In the T-group, one patient (0.2%) had an AUR. In CTRL, 23 patients (5.5%) had an AUR during the observation time (p &amp;lt; 0.0001 between groups). In the T-group, 60 men (14.7%) died. In CTRL, 171 patients (41.2%) died during the follow-up period (p &amp;lt; 0.0001 between groups). Conclusions Long-term TTh in men with functional hypogonadism was associated with the incidence of less adverse urological events and lower all-cause mortality, compared to an untreated control. Because of the observational design of the registry study, these findings have to be interpreted with caution. Disclosure Yes, this is sponsored by industry/sponsor: Gruenenthal GmbH, Aachen, Germany. Clarification: Industry funding only - investigator initiated and executed study. Any of the authors act as a consultant, employee or shareholder of an industry for: Gruenenthal GmbH, Aachen, Germany.