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Introduction: Low testosterone (T) levels are associated with obesity, metabolic syndrome, type 2 diabetes mellitus and altered lipid profiles, thus contributing to increased cardiovascular disease risk. Hence T deficiency has a detrimental effect on men's vascular health, quality of life and increased mortality., Objectives: This review aims to present summary of data in the contemporary clinical literature pertaining to the benefits of T therapy in clinical studies with varying durations on vascular health in men with T deficiency., Methods: A Medline search using PubMed and EMBASE was performed using the following key words: "testosterone deficiency," "testosterone therapy," major cardiovascular adverse events", "cardiovascular disease". Relevant studies were extracted, evaluated, and analyzed. We evaluated findings from clinical trials, observational studies and systematic reviews and meta-analyses to develop a comprehensive account of the critical role of T in maintaining vascular health., Results: Considerable evidence beginning with studies published in 1940s concomitant with findings from the utmost recent clinical studies suggests a clinical value of T therapy in maintaining vascular health and reducing cardiovascular mortality. The current scientific and clinical evidence demonstrates strong relationship between low circulating T levels and risk of cardiovascular disease and T therapy is deemed safe in men with hypogonadism when given in the physiological range with no apparent harm., Conclusion: What emerges from the current clinical literature is that, irrespective of the length of study durations, testosterone therapy provides significant health benefits and reduces risk of cardiovascular disease. More important is that data from many observational and registry studies, demonstrated that longer durations of testosterone therapy were associated with greater health benefits and reduced cardiovascular risk. T therapy in men with T deficiency reduces the incidence of major adverse cardiovascular events attributed to improving overall metabolic function., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Testosterone (T) deficiency (TD; hypogonadism) has deleterious effects on men's health; negatively affects glycometabolic and cardiometabolic functions, body composition, and bone mineral density; contributes to anemia and sexual dysfunction; and lowers quality of life. T therapy (TTh) has been used for the past 8 decades to treat TD, with positive effects on signs and symptoms of TD., Aim: To summarize the health benefits of TTh in men with TD., Methods: A comprehensive literature search was carried out using PubMed, articles relevant to TTh were accessed and evaluated, and a comprehensive summary was synthesized., Main Outcome Measures: Improvements in signs and symptoms of TD reported in observational studies, registries, clinical trials, and meta-analyses were reviewed and summarized., Results: A large body of evidence provides significant valuable information pertaining to the therapeutic value of TTh in men with TD. TTh in men with TD provides real health benefits for bone mineral density, anemia, sexual function, glycometabolic and cardiometabolic function, and improvements in body composition, anthropometric parameters, and quality of life., Conclusion: TTh in the physiologic range for men with TD is a safe and effective therapeutic modality and imparts great benefits on men's health and quality of life. Traish AM. Benefits and Health Implications of Testosterone Therapy in Men With Testosterone Deficiency. Sex Med Rev 2018;6:86-105., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: In the absence of large, prospective, placebo-controlled studies of longer duration, substantial evidence regarding the safety and risk of testosterone (T) therapy (TTh) with regard to cardiovascular (CV) outcomes can only be gleaned from observational studies. To date, there are limited studies comparing the effects of long-term TTh in men with hypogonadism who were treated or remained untreated with T, for obvious reasons. We have established a registry to assess the long-term effectiveness and safety of T in men in a urological setting. Here, we sought to compare the effects of T on a host of parameters considered to contribute to CV risk in treated and untreated men with hypogonadism (control group)., Patients and Methods: Observational, prospective, cumulative registry study in 656 men (age: 60.7 ± 7.2 years) with total T levels ≤12.1 nmol/L and symptoms of hypogonadism. In the treatment group, men (n = 360) received parenteral T undecanoate (TU) 1000 mg/12 weeks following an initial 6-week interval for up to 10 years. Men (n = 296) who had opted against TTh served as controls. Median follow-up in both groups was 7 years. Measurements were taken at least twice a year, and 8-year data were analyzed. Mean changes over time between the 2 groups were compared by means of a mixed-effects model for repeated measures, with a random effect for intercept and fixed effects for time, group, and their interaction. To account for baseline differences between the 2 groups, changes were adjusted for age, weight, waist circumference, fasting glucose, blood pressure, and lipids., Results: There were 2 deaths in the T-treated group, none was related to CV events. There were 21 deaths in the untreated (control) group, 19 of which were related to CV events. The incidence of death in 10 patient-years was 0.1145 in the control group (95% confidence interval [CI]: 0.0746-0.1756; P < .000) and 0.0092 in the T-treated group (95% CI: 0.0023-0.0368; P < .000); the estimated difference between groups was 0.0804 (95% CI: 0.0189-0.3431; P < .001). The estimated reduction in mortality for the T-group was between 66% and 92%. There were also 30 nonfatal strokes and 26 nonfatal myocardial infarctions in the control group and none in the T-treated group., Conclusion: Long-term TU was well tolerated with excellent adherence suggesting a high level of patient satisfaction. Mortality related to CV disease was significantly reduced in the T-group.

Androgens are steroid hormones with pleotropic and diverse biochemical and physiological functions, and androgen deficiency exerts a negative impact on human health. Testosterone (T) either directly or via its transformation into the more potent metabolite 5α-dihydrotestosterone (5α-DHT) or via aromatization into estradiol (E 2 ) modulates important biochemical signaling pathways of human physiology and plays a critical role in the growth and/or maintenance of functions in a host of tissues and organs. T and 5α-DHT play an important role in regulating physiology of the muscle, adipose tissue, liver, bone, and central nervous system, as well as reproductive and sexual functions. Thus, androgen deficiency (also referred to as hypogonadism) is a well-recognized medical condition and if remained untreated will have a negative impact on human health and quality of life.In this chapter, we have summarized the negative impact of T deficiency (TD) on a host of physiological functions including reduced lean body mass (LBM), increased fat mass (FM), increased insulin resistance (IR), metabolic syndrome (MetS) and adiposity, reduced bone mineral density (BMD), anemia, sexual dysfunction, and reduced quality of life and increased mortality. In addition, we discuss another critical aspect of unrecognized form of androgen deficiency resulting from inhibition of 5α-reductases with drugs, such as finasteride and dutasteride, to block transformation of T into 5α-DHT in the course of treatment of benign prostatic hyperplasia (BPH) and male pattern hair loss, also known as androgenetic alopecia (AGA). The negative impact of drugs that inhibit transformation of T to 5α-DHT by 5α-reductases on metabolic function is manifested in fat accumulation in the liver, which may predispose to nonalcoholic fatty liver disease (NAFLD). Also, inhibition of 5α-DHT formation increases glucose synthesis and reduces glucose disposal potentially contributing to hyperglycemia, IR, and elevated activities of liver function enzymes concomitant with reduction in circulating T levels, worsening erectile dysfunction (ED), and reduced quality of life.Although we have attempted to summarize the current literature pertaining to this critical topic "androgen deficiency" and its impact on men's health and quality of life, there remain many gaps in the knowledge regarding the biochemical pathways that are involved in the pathophysiology of androgen deficiency. We wish to clearly state that there are areas of controversies, including whether age-related androgen deficiency (functional hypogonadism) merits treatment and whether T therapy provided real proven benefits. Finally, considerable debate exists with respect to the potential and purported cardiovascular (CV) risks of treating TD with exogenous T. For brevity sake, we will not discuss in detail the benefits of T therapy in men with TD since this topic is comprehensively covered by Dr. F. Saad's chapter in this book, entitled "Testosterone Therapy and Glucose Homeostasis in Men with Testosterone Deficiency (Hypogonadism)."We have made a concerted effort to address the controversy of T therapy in men with TD in the discussion. However, we wish to acknowledge that these issues will remain a matter of debate for some time to come. Only with advances in fundamental basic science and clinical research, some of these controversial issues may be laid to rest. Nevertheless, we believe that there is considerable body of credible evidence to suggest that T therapy of men with TD is safe and effective and provides a host of health benefits and therefore merits considerations in men with TD, irrespective of the underlying cause or etiology. An additional aspect of androgen deficiency is the drug-induced reduction in 5α-DHT levels by the use of 5α-reductase inhibitors. We also believe that physicians prescribing 5α-reductase inhibitors (i.e., finasteride or dutasteride) for relief of BPH symptoms or treatment of hair loss should engage their patients in a productive discussion regarding the potential adverse side effects of these medications on their overall health and quality of life.

In the adult male, testosterone (T) deficiency (TD) also known as male hypogonadism, is a well-established medical condition, which has been recognized for more than a century. T therapy in men with TD was introduced as early as 1940s and was reported to improve overall health with no concomitant serious adverse effects. A wealth of recent studies demonstrated that T therapy in men with TD is associated with increased lean body mass, reduced fat mass and waist circumference, improvement in glycemic control, and reduced obesity. T therapy is also associated with improvements in lipid profiles, amelioration of metabolic syndrome (Met S) components, reduced inflammatory biomarkers, reduced systolic and diastolic blood pressure, and improvements in sexual function. More importantly, T therapy is associated with amelioration of diabetes and reduced mortality. However, few studies, marred with serious methodological and analytical flaws reported between 2010 and 2014, suggested that T therapy is associated with increased cardiovascular (CV) risk. As summarized in this review, a thorough and critical analysis of these studies showed that the risks purported are unsubstantiated and such studies lacked credible scientific and clinical evidence. Moreover, recent observational, registry studies, clinical trials, and meta-analyses, all revealed no increase in CV risks in men receiving T therapy. In this review, the benefits of T therapy in adult men with TD and the lack of credible evidence suggesting that T therapy is linked to increased CV risks are discussed. It should be noted that the literature is replete with studies demonstrating beneficial effects of T therapy on CV and overall health., (Copyright © 2016 the American Physiological Society.)

To address widespread concerns regarding the medical condition of testosterone (T) deficiency (TD) (male hypogonadism) and its treatment with T therapy, an international expert consensus conference was convened in Prague, Czech Republic, on October 1, 2015. Experts included a broad range of medical specialties including urology, endocrinology, diabetology, internal medicine, and basic science research. A representative from the European Medicines Agency participated in a nonvoting capacity. Nine resolutions were debated, with unanimous approval: (1) TD is a well-established, clinically significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life; (2) symptoms and signs of TD occur as a result of low levels of T and may benefit from treatment regardless of whether there is an identified underlying etiology; (3) TD is a global public health concern; (4) T therapy for men with TD is effective, rational, and evidence based; (5) there is no T concentration threshold that reliably distinguishes those who will respond to treatment from those who will not; (6) there is no scientific basis for any age-specific recommendations against the use of T therapy in men; (7) the evidence does not support increased risks of cardiovascular events with T therapy; (8) the evidence does not support increased risk of prostate cancer with T therapy; and (9) the evidence supports a major research initiative to explore possible benefits of T therapy for cardiometabolic disease, including diabetes. These resolutions may be considered points of agreement by a broad range of experts based on the best available scientific evidence., (Copyright © 2016 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: The 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 Findings: Long-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., Summary: The 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.

Here, we investigated how LDL receptor deficiency (Ldlr(-/-)) modulates the effects of testosterone on obesity and related metabolic dysfunctions. Though sham-operated Ldlr(-/-) mice fed Western-type diet for 12 weeks became obese and showed disturbed plasma glucose metabolism and plasma cholesterol and TG profiles, castrated mice were resistant to diet-induced obesity and had improved glucose metabolism and reduced plasma TG levels, despite a further deterioration in their plasma cholesterol profile. The effect of hypogonadism on diet-induced weight gain of Ldlr(-/-) mice was independent of ApoE and Lrp1. Indirect calorimetry analysis indicated that hypogonadism in Ldlr(-/-) mice was associated with increased metabolic rate. Indeed, mitochondrial cytochrome c and uncoupling protein 1 expression were elevated, primarily in white adipose tissue, confirming increased mitochondrial metabolic activity due to thermogenesis. Testosterone replacement in castrated Ldlr(-/-) mice for a period of 8 weeks promoted diet-induced obesity, indicating a direct role of testosterone in the observed phenotype. Treatment of sham-operated Ldlr(-/-) mice with the aromatase inhibitor exemestane for 8 weeks showed that the obesity of castrated Ldlr(-/-) mice is independent of estrogens. Overall, our data reveal a novel role of Ldlr as functional modulator of metabolic alterations associated with hypogonadism., (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)

Aim: The goal of this study was to determine if long-term testosterone (T) therapy in men with hypogonadism, henceforth referred to as testosterone deficiency (TD), ameliorates or improves metabolic syndrome (MetS) components., Methods: We performed a cumulative registry study of 255 men, aged between 33 and 69 years (mean 58.02 ± 6.30) with subnormal plasma total T levels (mean: 9.93 ± 1.38; range: 5.89-12.13 nmol/l) as well as at least mild symptoms of TD assessed by the Aging Males' symptoms scale. All men received treatment with parenteral T undecanoate 1000 mg (Nebido(®) , Bayer Pharma, Berlin, Germany), administered at baseline and 6 weeks and thereafter every 12 weeks for up to 60 months. Lipids, glucose, liver enzymes and haemoglobin A1c analyses were carried out in a commercial laboratory. Anthropometric measurements were also made throughout the study period., Results: Testosterone therapy restored physiological T levels and resulted in reductions in total cholesterol (TC) [7.29 ± 1.03 to 4.87 ± 0.29 mmol/l (281.58 ± 39.8 to 188.12 ± 11.31 mg/dl)], low-density lipoprotein cholesterol [4.24 ± 1.07 to 2.84 ± 0.92 mmol/l (163.79 ± 41.44 to 109.84 ± 35.41 mg/dl)], triglycerides [3.14 ± 0.58 to 2.16 ± 0.13 mmol/l (276.16 ± 51.32 to 189.78 ± 11.33 mg/dl)] and increased high-density lipoprotein levels [1.45 ± 0.46 to 1.52 ± 0.45 mmol/l (56.17 ± 17.79 to 58.85 ± 17.51 mg/dl)] (p < 0.0001 for all). There were marked reductions in systolic and diastolic blood pressure, blood glucose, haemoglobin A1c , C-reactive protein (6.29 ± 7.96 to 1.03 ± 1.87 U/l), alanine aminotransferase and aspartate aminotransferase (p < 0.0001 for all)., Conclusions: Long-term T therapy, at physiological levels, ameliorates MetS components. These findings strongly suggest that T therapy in hypogonadal men may prove useful in reducing the risk of cardiometabolic diseases., (© 2013 The Authors. International Journal of Clinical Practice Published by John Wiley & Sons Ltd.)

Testosterone deficiency (TD) afflicts approximately 30% of men aged 40-79 years, with an increase in prevalence strongly associated with aging and common medical conditions including obesity, diabetes, and hypertension. A strong relationship is noted between TD and metabolic syndrome, although the relationship is not certain to be causal. Repletion of testosterone (T) in T-deficient men with these comorbidities may indeed reverse or delay their progression. While T repletion has been largely thought of in a sexual realm, we discuss its potential role in general men's health concerns: metabolic, body composition, and all-cause mortality through the use of a single clinical vignette. This review examines a host of studies, with practical recommendations for diagnosis of TD and T repletion in middle-aged and older men, including an analysis of treatment modalities and areas of concerns and uncertainty., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The metabolic syndrome (MetS) is considered the most important public health threat of the 21st century. This syndrome is characterized by a cluster of cardiovascular risk factors including increased central abdominal obesity, elevated triglycerides, reduced high-density lipoprotein, high blood pressure, increased fasting glucose, and hyperinsulinemia. These factors increase the risk of cardiovascular disease (CVD) and/or type 2 diabetes. Although the etiology of this syndrome is thought to stem from obesity and physical inactivity, the extent of interactions of the individual MetS components with one another remains poorly defined. Obesity, diabetes, hypogonadism, and specific hormone and metabolic profiles have been implicated in the pathophysiology of CVD. The evolving role of androgens in MetS and CVD is of paramount importance. Reduced androgen levels associated with hypogonadism or androgen deprivation therapy increase cardiovascular risk factors and produce marked adverse effects on cardiovascular function. MetS has been associated with hypogonadism and erectile dysfunction (ED), and MetS may be considered a risk factor for ED. It is suggested that MetS, diabetes, and CVD will increase in the upcoming decades. Thus, it is critically important to develop a better understanding of how obesity, diabetes and hypogonadism contribute to androgen deficiency and the various pathophysiologic states of vascular disease. In this review we discuss the current literature pertaining to androgen deficiency, MetS, and ED, because the relationship of these factors is of scientific and clinical importance. Specifically, we will focus on exploring the relationships between hypogonadism, obesity, MetS, and ED.

Objectives: Androgens are essential for the development and growth of the penis, and they regulate erectile physiology by multiple mechanisms. Our goal is to provide a concise overview of the basic research and how this knowledge can be translated into a new clinical paradigm for patient management. In addition, this new paradigm may serve as a basis for stimulating constructive debate regarding the use of testosterone in men, and to promote new, innovative basic and clinical research to further understand the underlying mechanisms of androgen action in restoring erectile physiology., Methods: A literature review was performed utilizing the US National Library of Medicine's PubMed database., Results: On the basis of evidence derived from laboratory animal studies and clinical data, we postulate that androgen insufficiency disrupts cellular-signaling pathways and produces pathologic alterations in penile tissues, leading to erectile dysfunction. In this review, we discuss androgen-dependent cellular, molecular, and physiologic mechanisms modulating erectile function in the animal model, and the implication of this knowledge in testosterone use in the clinical setting to treat erectile dysfunction. The new clinical paradigm incorporates many of the consensed points of view discussed in traditional consensed algorithms exclusively designed for men with androgen insufficiency. There are, however, novel and innovative differences with this new clinical paradigm. This paradigm represents a fresh effort to provide mandatory and optional management strategies for men with both androgen insufficiency and erectile dysfunction., Conclusions: The new clinical paradigm is evidence-based and represents one of the first attempts to address a logical management plan for men with concomitant hormonal and sexual health concerns.