Major cardiovascular disease risk in men with testosterone deficiency (hypogonadism): appraisal of short, medium and long-term testosterone therapy - a narrative review.

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.

Sex steroids and COVID-19 mortality in women.

More men died of coronavirus disease 2019 (COVID-19) than women, suggesting estrogens may protect women. However, COVID-19 deaths among men and women were inconsistent among countries throughout the world. Genetics, epigenetics, and inborn errors of immunity may account for the disparity in mortality among men and women with COVID-19 more than sex steroid hormones.

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women.

BACKGROUND: The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal women with hypoactive sexual desire disorder (HSDD). AIM: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with HSDD. METHODS: The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method. OUTCOMES: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up. RESULTS: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data. CLINICAL IMPLICATIONS: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring. STRENGTHS & LIMITATIONS: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging. CONCLUSION: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need. Parish SJ, Simon JA, Davis SR, et al. International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women. J Sex Med 2021;18:849-867.

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women.

Background: The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal women with hypoactive sexual desire disorder (HSDD). Aim: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with HSDD. Methods: The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method. Outcomes: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up. Results: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data. Clinical Implications: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring. Strengths & Limitations: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging. Conclusion: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need.

International Society for the Study of Women's Sexual Health Clinical Practice Guideline for the Use of Systemic Testosterone for Hypoactive Sexual Desire Disorder in Women.

AIM: To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with hypoactive sexual desire disorder (HSDD). METHODS: The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method. OUTCOMES: A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up. RESULTS: Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data. CLINICAL IMPLICATIONS: This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring. STRENGTHS AND LIMITATIONS: This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging. CONCLUSION: Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need.

Health Risks Associated with Long-Term Finasteride and Dutasteride Use: It's Time to Sound the Alarm.

5α-dihydrotestosterone (5α-DHT) is the most potent natural androgen. 5α-DHT elicits a multitude of physiological actions, in a host of tissues, including prostate, seminal vesicles, hair follicles, skin, kidney, and lacrimal and meibomian glands. However, the physiological role of 5α-DHT in human physiology, remains questionable and, at best, poorly appreciated. Recent emerging literature supports a role for 5α-DHT in the physiological function of liver, pancreatic ß-cell function and survival, ocular function and prevention of dry eye disease and kidney physiological function. Thus, inhibition of 5α-reductases with finasteride or dutasteride to reduce 5α-DHT biosynthesis in the course of treatment of benign prostatic hyperplasia (BPH) or male pattern hair loss, known as androgenetic alopecia (AGA) my induces a novel form of tissue specific androgen deficiency and contributes to a host of pathophysiological conditions, that are yet to be fully recognized. Here, we advance the concept that blockade of 5α-reductases by finasteride or dutasteride in a mechanism-based, irreversible, inhabitation of 5α-DHT biosynthesis results in a novel state of androgen deficiency, independent of circulating testosterone levels. Finasteride and dutasteride are frequently prescribed for long-term treatment of lower urinary tract symptoms in men with BPH and in men with AGA. This treatment may result in development of non-alcoholic fatty liver diseases (NAFLD), insulin resistance (IR), type 2 diabetes (T2DM), dry eye disease, potential kidney dysfunction, among other metabolic dysfunctions. We suggest that long-term use of finasteride and dutasteride may be associated with health risks including NAFLD, IR, T2DM, dry eye disease and potential kidney disease.

Post-finasteride syndrome: a surmountable challenge for clinicians.

Post-finasteride syndrome (PFS) is a constellation of serious adverse side effects manifested in clinical symptoms that develop and persist in patients during and/or after discontinuing finasteride treatment in men with pattern hair loss (androgenetic alopecia) or benign prostatic hyperplasia. These serious adverse side effects include persistent or irreversible sexual, neurological, physical and mental side effects. To date, there are no evidence-based effective treatments for PFS. Although increasing number of men report persistent side effects, the medical community has yet to recognize this syndrome nor are there any specific measures to address this serious and debilitating symptoms. Here we evaluate the scientific and clinical evidence in the contemporary medical literature to address the very fundamental question: Is PFS a real clinical condition caused by finasteride use or are the reported symptoms only incidentally associated with but not caused by finasteride use? One key indisputable clinical evidence noted in all reported studies with finasteride and dutasteride was that use of these drugs is associated with development of sexual dysfunction, which may persist in a subset of men, irrespective of age, drug dose or duration of study. Also, increased depression, anxiety and suicidal ideation in a subset of men treated with these drugs were commonly reported in a number of studies. It is important to note that many clinical studies suffer from incomplete or inadequate assessment of adverse events and often limited or inaccurate data reporting regarding harm. Based on the existing body of evidence in the contemporary clinical literature, the author believes that finasteride and dutasteride induce a constellation of persistent sexual, neurological and physical adverse side effects, in a subset of men. These constellations of symptoms constitute the basis for PFS in individuals predisposed to epigenetic susceptibility. Indeed, delineating the pathophysiological mechanisms underlying PFS will be of paramount importance to the understanding of this syndrome and to development of potential novel therapeutic modalities.

Do 5α-Reductase Inhibitors Raise Circulating Serum Testosterone Levels? A Comprehensive Review and Meta-Analysis to Explaining Paradoxical Results.

INTRODUCTION: Many studies have reported that 5α-reductase inhibitors (finasteride and dutasteride) raise serum testosterone (T) levels, yet there is lack of consistency among studies on this point. AIM: To review and meta-analyze available studies reporting changes in serum T concentrations in men treated with 5α-reductase inhibitors (5α-RIs). METHODS: A Medline search using PubMed and EMBASE was performed including the following key words: "finasteride," "dutasteride," "testosterone and 5α-reductases." MAIN OUTCOME MEASURE: Relevant studies were extracted, evaluated, and analyzed. Of these, 40 studies were analyzed qualitatively and 11 were included in the meta-analysis. A random effects model was used to conduct the meta-analysis. RESULTS: In 11 studies comprising 1,784 patients with age ranging between 18 and 83 years and average treatment follow-up of 17 months, meta-analytic estimate of the mean baseline change was 27 (95% confidence interval 1-54). The meta-analysis did not demonstrate unequivocal significant increase in serum T levels. The increase was not uniform among all studies reported. Sensitivity analysis showed that no single study contributed decisively to the outcome or could be attributed to drug action. The reported increases in T levels with finasteride or dutasteride in men with low baseline serum T may be attributed, in part, to increased trapping of T by unsaturated sex hormone binding globulin (SHBG) due to dissociation of 5α-dihydrotestosterone. In men with high baseline T levels, there appears to be no change in serum T levels. 10 studies reported luteinizing hormone, follicle-stimulating hormone, SHBG, and estradiol values and none reported significant changes in their levels, suggesting that observed changes in serum T levels are unlikely mediated by gonadotropins levels or peripheral conversion of T to estradiol. CONCLUSION: 5α-RI therapy is not associated with consistent and significant increases in serum T levels. Traish AM, Krakowsky Y, Doros G, et al. Do 5α-reductase inhibitors raise circulating serum testosterone levels? A comprehensive review and meta-analysis to explaining paradoxical results. Sex Med Rev 2019;7:95-114.

Impact of Testosterone Deficiency and Testosterone Therapy on Lower Urinary Tract Symptoms in Men with Metabolic Syndrome.

Lower urinary tract function is modulated by neural, vascular and urethral and bladder structural elements. The pathophysiological mechanisms of lower urinary tract symptoms (LUTS) encompass prostate enlargement, alterations in urethra histological structure bladder fibrosis and alterations in pelvic neuronal and vascular networks, The complex pathophysiological relationship between testosterone (T) deficiency (TD) and the constellations LUTS, and metabolic dysfunction manifested in the metabolic syndrome (Met S) remains poorly understood. TD has emerged as one the potential targets by which Met S may contribute to the onset and development as well as worsening of LUTS. Because it has been recognized that treatment of men with Met S with T therapy ameliorates Met S components, it is postulated that T therapy may represent a therapeutic target in improving LUTS. Furthermore, the effect of TD on the prostate remains unclear, and often debatable. It is believed that T exclusively promotes prostate growth, however recent evidence has strongly contradicted this belief. The true relationship between benign prostatic hyperplasia, TD, and LUTS remains elusive and further research will be required to clarify the role of T in both benign prostatic hypertrophy (BPH) and LUTS as a whole. Although there is conflicting evidence about the benefits of T therapy in men with BPH and LUTS, the current body of literature supports the safety of using this therapy in men with enlarged prostate. As the population afflicted with obesity epidemic continues to age, the number of men suffering from Met S and LUTS together is expected to increase.

The role of androgens in the treatment of genitourinary syndrome of menopause (GSM): International Society for the Study of Women's Sexual Health (ISSWSH) expert consensus panel review.

OBJECTIVE: The objective of this consensus document is to broaden the perspective on clinical management of genitourinary syndrome of menopause to include androgens. METHODS: A modified Delphi method was used to reach consensus among the 14 international panelists representing multiple disciplines and societies. RESULTS: Menopause-related genitourinary symptoms affect over 50% of midlife and older women. These symptoms have a marked impact on sexual functioning, daily activities, emotional well-being, body image, and interpersonal relations. Tissues in the genitourinary system are both androgen and estrogen-dependent. The clitoris, vestibule, including minor and major vestibular glands, urethra, anterior vaginal wall, periurethral tissue, and pelvic floor are androgen-responsive. Historically, treatment of postmenopausal genitourinary symptoms involved both androgens and estrogens. This subsequently gave rise to predominantly estrogen-based therapies. More recently, double-blind, placebo-controlled clinical trials have demonstrated that local vaginal dehydroepiandrosterone improves symptoms in postmenopausal women, including moderate to severe dyspareunia. Limited data suggest that systemic testosterone treatment may improve vaginal epithelial health and blood flow. Open-label studies that have used high doses of intravaginal testosterone in the presence of aromatase inhibitor therapy for breast cancer have resulted in supraphysiological serum testosterone levels, and have been reported to lower vaginal pH, improve the vaginal maturation index, and reduce dyspareunia. CONCLUSIONS: Vaginal dehydroepiandrosterone, hypothesized to enhance local production of both androgen and estrogen, is effective for the management of dyspareunia in menopause. Vaginal testosterone offers potential as a treatment for genitourinary syndrome of menopause, but more studies are needed.

Role of Androgens in Female Genitourinary Tissue Structure and Function: Implications in the Genitourinary Syndrome of Menopause.

INTRODUCTION: Genitourinary conditions in women increase in prevalence with age. Androgens are prerequisite hormones of estrogen biosynthesis, are produced in larger amounts than estrogens in women, and decrease throughout adulthood. However, research and treatment for genitourinary complaints have traditionally focused on estrogens to the exclusion of other potential hormonal influences. AIM: To summarize and evaluate the evidence that androgens are important for maintaining genitourinary health in women and that lack of androgenic activity can contribute to the development of symptoms of the genitourinary syndrome of menopause. METHODS: The role of androgens in the pathophysiology, diagnosis, and treatment of genitourinary syndrome of menopause was discussed by an international and multidisciplinary panel during a consensus conference organized by the International Society for the Study of Women's Sexual Health. A subgroup further examined publications from the PubMed database, giving preference to clinical studies or to basic science studies in human tissues. MAIN OUTCOME MEASURES: Expert opinion evaluating trophic and functional effects of androgens, their differences from estrogenic effects, and regulation of androgen and estrogen receptor expression in female genitourinary tissues. RESULTS: Androgen receptors have been detected throughout the genitourinary system using immunohistochemical, western blot, ligand binding, and gene expression analyses. Lower circulating testosterone and estradiol concentrations and various genitourinary conditions have been associated with differential expression of androgen and estrogen receptors. Supplementation of androgen and/or estrogen in postmenopausal women (local administration) or in ovariectomized animals (systemic administration) induces tissue-specific responses that include changes in androgen and estrogen receptor expression, cell growth, mucin production, collagen turnover, increased perfusion, and neurotransmitter synthesis. CONCLUSION: Androgens contribute to the maintenance of genitourinary tissue structure and function. The effects of androgens can be distinct from those of estrogens or can complement estrogenic action. Androgen-mediated processes might be involved in the full or partial resolution of genitourinary syndrome of menopause symptoms in women. Traish AM, Vignozzi L, Simon JA, et al. Role of Androgens in Female Genitourinary Tissue Structure and Function: Implications in the Genitourinary Syndrome of Menopause. Sex Med Rev 2018;6:558-571.

The state of testosterone therapy since the FDA's 2015 labelling changes: Indications and cardiovascular risk.

OBJECTIVE: A label change in testosterone (T) products in March 2015 followed a highly publicized FDA advisory committee meeting in September 2014. Changes included a warning of possible increased cardiovascular (CV) risks and restriction of indicated populations to younger men with a limited set of known aetiologies of testosterone deficiency (TD). These changes greatly impacted clinical practice and public perception of T therapy (TTh). Our aim was to review these changes in the light of subsequently published studies. DESIGN: We identified 23 studies through June 2017, including 12 clinical trials and 11 observational studies. The Testosterone Trials included 790 men aged 65 years and older with TD without known aetiology, assigned to 1-year T gel or placebo. RESULTS: Demonstrated benefits of T included sexual activity and desire, physical activity and mood. There were 9 major adverse CV events (MACE) in the T arm and 16 in the placebo arm. No study reported increased MACE with TTh. A 3-year RCT showed no difference in carotid atherosclerosis. Several large observational studies reported reduced CV events with TTh, including one showing progressively reduced CV and mortality risk with greater duration of TTh. Men whose serum T normalized with TTh had reduced risk of MI and death compared with men whose T levels failed to normalize. CONCLUSION: We conclude that existing evidence fails to support increased CV risk with TTh; on the contrary, there is evidence suggestive of real-world CV benefits. Finally, existing evidence provides benefits of TTh in older men without known aetiology for T deficiency.

Benefits and Health Implications of Testosterone Therapy in Men With Testosterone Deficiency.

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.

Negative Impact of Testosterone Deficiency and 5α-Reductase Inhibitors Therapy on Metabolic and Sexual Function in Men.

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 (E2) 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.

Long-Term Testosterone Therapy Improves Cardiometabolic Function and Reduces Risk of Cardiovascular Disease in Men with Hypogonadism: A Real-Life Observational Registry Study Setting Comparing Treated and Untreated (Control) Groups.

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.

Testosterone therapy in men with testosterone deficiency: are the benefits and cardiovascular risks real or imagined?

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.