Men, testosterone and Covid-19.

Men have more severe Coronavirus disease 2019 (Covid-19) outcomes and higher mortality rates than women, and it was suggested that testosterone levels might promote severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and Covid-19 severity. However, clinical studies have not supported this theory. Studies have consistently shown that serum testosterone concentrations during acute Covid-19 in men are inversely proportional to the inflammatory cytokines and severity of illness. It is likely that lower testosterone concentrations in this setting are a result of acute Covid-19 illness on the hypothalamic-pituitary-testicular axis. Clinical trials that attempted to lower testosterone concentrations further or block androgen signaling acutely during Covid-19 in men did not result in improved Covid-19 outcomes. Additionally, pre-existing male hypogonadism, diagnosed before Covid-19 pandemic, was found to be a risk factor for hospitalization from Covid-19. In this review, we also discuss the preclinical and mechanistic studies that have evaluated the role of androgens in SARS-CoV-2 infection and illness. Finally, long-term consequences of Covid-19 on male reproductive health are reviewed. SARS-CoV-2 virus is known to infiltrate testis and induce orchitis in men, but it is unclear if Covid-19 leads to an increase in incidence of male hypogonadism.

Important lessons about testosterone therapy- weight loss vs. testosterone therapy for symptom resolution, classical vs. functional hypogonadism, and shortterm vs. lifelong testosterone therapy.

In this commentary, we highlight important findings from a notable RCT by Ng Tang Fui et al. 2016 which investigated the effects of testosterone treatment in dieting obese men. First, a myopic focus on weight loss can detract from important improvements in body composition. Second, while weight loss in obese men may increase testosterone levels, this increase is commonly not enough to result in an improvement in symptoms associated with testosterone deficiency. Third, the RCT by Ng Tang Fui et al. adds evidence to the growing number of clinical trials showing that testosterone therapy should not be restricted to men with classical hypogonadism. Finally, the beneficial effects of testosterone therapy are not maintained after cessation of treatment. Currently, the British Society for Sexual Medicine guidelines are the only clinical guidelines which acknowledge that weight loss per se does not automatically translate to resolution of hypogonadal symptoms, that testosterone therapy can greatly benefit men with testosterone deficiency who do not have classical hypogonadism, and that cessation of testosterone therapy causes reappearance of symptoms and reversal of benefits. Lifelong testosterone therapy is therefore recommended for persistent health benefits in most men with testosterone deficiency. Physicians and patients need to be informed of this.

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.

Testosterone therapy for prevention and reversal of type 2 diabetes in men with low testosterone.

Men with obesity and/or type 2 diabetes (T2D) have a high prevalence of testosterone deficiency (TD). Similarly, men with TD have an increased risk of developing obesity and/or T2D, and further body fat accumulation and deterioration of glycemic control create a vicious cycle. The landmark testosterone for diabetes mellitus trial, the largest randomized controlled trial of testosterone therapy (TTh) to date, confirms the beneficial effects of TTh on fat loss and gain in muscle mass, and that TTh for 2 years significantly reduces the risk of incident T2D, and may also reverse T2D. The testosterone for diabetes mellitus trial suggests that TTh reduces the risk of T2D and results in greater improvement in sexual function and wellbeing, beyond lifestyle intervention alone.

Safety of testosterone therapy in men with prostate cancer.

Introduction: 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.

Testosterone Therapy in Men With Hypogonadism Prevents Progression From Prediabetes to Type 2 Diabetes: Eight-Year Data From a Registry Study.

OBJECTIVE: Type 2 diabetes (T2D) is a public health threat. Prediabetes represents a window of opportunity for intervention to prevent T2D. Men with T2D and prediabetes often have low testosterone. Since testosterone improves glycemic control in T2D, we investigated whether testosterone therapy (TTh) in men with hypogonadism and prediabetes prevents progression to T2D. RESEARCH DESIGN AND METHODS: Three hundred and sixteen men with prediabetes (defined as HbA1c 5.7-6.4%) and total testosterone levels ≤12.1 nmol/L combined with symptoms of hypogonadism were analyzed. Two hundred and twenty-nine men received parenteral testosterone undecanoate (T-group), and 87 men with hypogonadism served as untreated control subjects. Metabolic and anthropometric parameters were measured twice yearly for 8 years. RESULTS: HbA1c decreased by 0.39 ± 0.03% (P < 0.0001) in the T-group and increased by 0.63 ± 0.1% (P < 0.0001) in the untreated group. In the T-group, 90% achieved normal glucose regulation (HbA1c <5.7%). In the untreated group, 40.2% progressed to T2D (HbA1c >6.5%). TTh was also associated with significant improvements in fasting glucose, triglyceride:HDL ratio, triglyceride-glucose index, lipid accumulation product, total cholesterol, LDL, HDL, non-HDL, triglycerides, and Aging Males' Symptoms (AMS) scale. Significant deterioration in all these parameters was seen in the untreated group. Mortality was 7.4% in the T-group and 16.1% in the untreated group (P < 0.05). The incidence of nonfatal myocardial infarction was 0.4% in the T-group and 5.7% in the untreated group (P < 0.005). CONCLUSIONS: Long-term TTh completely prevents prediabetes progression to T2D in men with hypogonadism and improves glycemia, lipids, and AMS score. TTh holds tremendous potential for the large and growing population of men with prediabetes and hypogonadism.

Testosterone therapy and cardiovascular risk: advances and controversies.

Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks. A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned. Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. In summary, there is no convincing evidence of increased CV risks with T therapy. On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.