Testosterone Therapy in Men with Klinefelter Syndrome: Analysis of a Global Federated Research Network.

(070) Testosterone Therapy in Men with Klinefelter Syndrome: Analysis of a Global Federated Research Network

37-Year-Old Man With Fatigue and Erectile Dysfunction

MP43-06 TESTOSTERONE THERAPY IN MEN WITH KLINEFELTER SYNDROME: ANALYSIS OF A GLOBAL FEDERATED RESEARCH NETWORK

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.

Testosterone deficiency has been reported in patients with Parkinson disease (PD), Alzheimer disease, and Huntington disease. It is not known whether testosterone therapy (TT) in men with borderline hypogonadism and neurodegenerative diseases will be of substantial benefit. Previously, we reported that testosterone deficiency is more common in patients with PD compared with age-matched control subjects, and we also reported in 2 small open-label studies that some nonmotor symptoms responded favorably to TT. To define the effects of TT on nonmotor and motor symptoms in men with PD and probable testosterone deficiency. Double-masked, placebo-controlled, parallel-group, single-center trial. Two experimental groups: patients with PD who were receiving either TT or placebo. Participants received either the study drug by intramuscular injection (200 mg/mL of testosterone enanthate every 2 weeks for 8 weeks) or placebo (isotonic sodium chloride solution injections). In patients in each group, the testosterone serum concentration was obtained at each study visit. During 2 study visits, testosterone levels were blindly evaluated and the intramuscular testosterone dose was increased by 200 mg/mL if the free testosterone value failed to double from the baseline value. The primary outcome variable was the St Louis Testosterone Deficiency Questionnaire, and secondary outcome measures included measures of mood, cognition, fatigue, motor function, and frequency of adverse events. At the end of the double-blind phase, all patients were offered open-label TT and were followed up after 3 and 6 months. Fifteen patients in the placebo group (mean age, 69.9 years), receiving a mean total levodopa equivalent dose of 924 mg/d, had a baseline free testosterone level of 47.91 pg/mL, compared with 15 patients in the TT group (mean age, 66.7 years), receiving an average total levodopa equivalent dose of 734 mg/d, who had a baseline free testosterone level of 63.49 pg/mL. Testosterone was generally well tolerated. More subjects in the TT group experienced lower extremity edema (40% vs 20%). In 2 patients, 1 in each group, prostate-specific antigen levels were elevated from baseline. The improvement in the TT group compared with the placebo group (1.7 vs 1.1) on the St Louis Testosterone Deficiency Scale was not statistically significant. In addition, there were no significant differences in motor and nonmotor features of PD between the 2 groups, although a few subscales showed improvements (Hopkins Verbal Learning Test, P<.04; and Backward Visual Span subtrial, P<.03). However, long-term open-label TT resulted in delayed but sustained improvement in subjects in the TT group who continued to receive treatment (n = 6) compared with subjects in the placebo group who elected not to receive TT (n = 3). Testosterone therapy was generally well tolerated in elderly men with PD and probable testosterone deficiency. While there was no significant difference in the motor and nonmotor scales between the TT and placebo groups at the end of 8 weeks compared with baseline, this may be due to several study limitations, including small sample size, a strong placebo effect with intramuscular therapy, and short follow-up that did not allow measurement of delayed effects of TT in some subjects. Until more definitive studies are reported, practitioners should be particularly cautious in treatment of low testosterone concentrations in men with PD and borderline testosterone deficiency, and careful consideration should be given to the risks vs the benefits of TT.

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.

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

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

Research in brief

It's not all about the testes: medical issues in Klinefelter patients

Trends in Testosterone Therapy use in Prostate Cancer Survivors in the United States

Testosterone replacement therapy for men with organic hypogonadism due to medical disease of the hypothalamic-pituitary-testicular (HPT) axis is uncontroversial. In these men, testosterone replacement replaces the deficient hormone and relieves the signs and symptoms of androgen deficiency. In contrast, the role of testosterone treatment in middle-aged or older men who have clinical features consistent with androgen deficiency accompanied by reductions in serum testosterone but lack identifiable HPT axis disease, a scenario sometimes referred to as 'functional' or 'late onset' hypogonadism, has been uncertain. Three large randomized controlled clinical trials, discussed in this review, have reported new data regarding short-term to medium-term benefits and risks of testosterone therapy in such middle-aged and older men, including effects on sexual function, vitality, cognition and mood, glucose metabolism, physical function, hematologic parameters, as well as bone, cardiovascular and prostate health. The findings of these trials allow for a more nuanced, personalized approach to testosterone therapy in such men. However, long-term benefits and risk of testosterone therapy (beyond 3-4 years) remain unknown.

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.

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

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.