Search

The Androgen Society is an international, multidisciplinary medical organization committed to advancing research and education in the field of testosterone deficiency and testosterone therapy (TTh). This position paper is written in response to results of the TRAVERSE study, published in June 2023, which reported no increased risk of major adverse cardiovascular events (MACE) in men who received TTh compared with placebo. In 2013-2014, 2 observational studies reported increased cardiovascular (CV) risks with TTh and received wide media attention. Despite strong criticism of those 2 studies, in 2015, the Food and Drug Administration added a CV warning to testosterone product labels and required pharmaceutical companies to perform a CV safety study, which became the TRAVERSE trial. TRAVERSE enrolled 5246 men at high risk for MACE based on existing heart disease or multiple risk factors. Participants were randomized to daily testosterone gel or placebo gel, with a mean follow-up of 33 months. Results revealed no greater risk of MACE (myocardial infarction, stroke, or CV death) or venothrombotic events in men who received TTh compared with placebo. Review of the prior literature reveals near uniformity of studies reporting no increased MACE with TTh. This includes 2 additional large randomized controlled trials, multiple smaller randomized controlled trials, several large observational studies, and 19 meta-analyses. In view of these findings, it is the position of the Androgen Society that it has now been conclusively determined that TTh is not associated with increased risks of heart attack, stroke, or CV death., (Copyright © 2024 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2018 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

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., (© 2018 John Wiley & Sons Ltd.)

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.

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.)

Testosterone deficiency (TD) is a well-established and recognized medical condition that contributes to several co-morbidities, including metabolic syndrome, visceral obesity and cardiovascular disease (CVD). More importantly, obesity is thought to contribute to TD. This complex bidirectional interplay between TD and obesity promotes a vicious cycle, which further contributes to the adverse effects of TD and obesity and may increase the risk of CVD. Testosterone (T) therapy for men with TD has been shown to be safe and effective in ameliorating the components of the metabolic syndrome (Met S) and in contributiong to increased lean body mass and reduced fat mass and therefore contributes to weight loss. We believe that appropriate T therapy in obese men with TD is a novel medical approach to manage obesity in men with TD. Indeed, other measures of lifestyle and behavioral changes can be used to augment but not fully replace this effective therapeutic approach. It should be noted that concerns regarding the safety of T therapy remain widely unsubstantiated and considerable evidence exists supporting the benefits of T therapy. Thus, it is paramount that clinicians managing obese men with TD be made aware of this novel approach to treatment of obesity. In this review, we discuss the relationship between TD and obesity and highlight the contemporary advancement in management of obesity with pharmacological and surgical approaches, as well as utilization of T therapy and how this intervention may evolve as a novel approach to treatment of obesity in men with TD .

Background: 5α-reductase inhibitors (5α-RIs) (finasteride and dutasteride) have been proven useful in treatment of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH). However, these inhibitors exert undesirable sexual side effects and, in some cases, these effects are persistent. There is considerable disagreement with regard to whether the adverse side effects resolve with continuous treatment., Aim: To investigate the long-term adverse effects of finasteride treatment in men with BPH on erectile function and to compare these adverse effects in men treated with the α1-adrenergic receptor blocker, tamsolusin., Methods: In this retrospective registry study, a cohort of 470 men aged between 47 and 68 years (mean 57.78±4.81) were treated with finasteride (5 mg/day). A second cohort of 230 men aged between 52 and 72 years (mean 62.62±4.65) were treated with tamsulosin (0.4 mg). All men were followed up for 45 months. At intervals of 3 months and at each visit, plasma testosterone (T) levels and the international index of erectile function (IIEF-EF) questionnaire scores were determined., Results: Long-term treatment with finasteride therapy is associated with worsening of erectile dysfunction (ED) as shown by the significant decrease in the IIEF-EF scores in men treated with finasteride. No worsening of ED was observed in men treated with tamsulosin. The increase in ED due to finasteride did not resolve with continued treatment with finasteride. Most importantly, long-term finasteride therapy resulted in reduction in total T levels, contributing to a state of hypogonadism. On the contrary, no changes in T levels were noted in men treated with tamsolusin., Conclusion: Our findings suggest that in men with BPH, long-term finasteride therapy but not tamsulosin results in worsening of ED and reduces total T concentrations. Clinicians are urged to discuss the impact of 5α-RIs therapy on sexual function with their patients before commencing this therapy.

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.

An international expert consensus conference regarding testosterone deficiency (TD) (also known as hypogonadism) and its treatment was held on 1 October 2015, in Prague, Czech Republic. The impetus for this meeting was to address several key scientific issues that have been misunderstood or distorted during the recent intense media attention to this topic. Eighteen experts from 11 countries participated, from the disciplines of urology, endocrinology, andrology, diabetology, and basic science research. The goal was to identify scientific concepts for which there was broad agreement. It was noted that recent public controversies regarding testosterone therapy have been anchored by two retrospective studies reporting increased cardiovascular (CV) risks. Both these studies contained major flaws, and are contradicted by a large body of evidence suggesting CV benefits with testosterone therapy. Other topics discussed included the negative impact of TD on male health; the questionable validity of restrictions on treatment based on age-specific cut-offs, presence of identified underlying conditions, or application of rigid biochemical thresholds; and the lack of evidence regarding prostate cancer risks. Final consensus statements (resolutions) are under development. It is hoped these will serve as a scientific foundation for further discussion, and will thereby reduce misinformation regarding TD and its treatment.

Testosterone (T) deficiency (TD) is a common clinical condition, which contributes to co-morbidities including loss of muscle mass, increased fat mass, increased inflammation, insulin resistance, risk of vascular disease, sexual dysfunction, fatigue, depressed mood and reduced quality of life. T therapy attenuates inflammation, increases insulin sensitivity, muscle mass and reduces fat mass and adiposity. T therapy improves lipid profiles and endothelial function and reduces systolic and diastolic blood pressure. In addition, T therapy may reduce risk of vascular disease and mortality. T therapy improves bone mineral density and increases energy and vitality and improves mood and sexual function and overall quality of life. T therapy appears to be safe if treatment and monitoring are appropriately executed. The evidence available to date does not support alleged concerns regarding risk of cardiovascular disease and prostate cancer. Indeed, T therapy remains controversial. The data in the contemporary literature suggest that T therapy reduces cardiovascular risk and fears promoted by some recent studies should be re-evaluated. The cardiovascular risk and mortality with T therapy must await large prospective controlled clinical trials, which depend on many complex factors. Such studies may be prohibitive in the current environment due to logistical challenges, such as recruiting large number of men to be treated for long-durations with appropriate follow-up, requiring astronomical cost., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Testosterone and its metabolite, 5α-dihydrotestosterone are critical metabolic and vascular hormones, which regulate a host of biochemical pathways including carbohydrate, lipid and protein metabolism and modulate vascular function. Testosterone deficiency (TD) is a well-recognized medical condition with important health implications. TD is associated with a number of co-morbidities including increased body weight, adiposity and increased waist circumference, insulin resistance (IR) and type 2 diabetes mellitus (T2DM), hypertension, inflammation, atherosclerosis and cardiovascular disease, erectile dysfunction (ED) and increased incidence of mortality. In this review, we summarize the data in the literature on the prevalence of TD and its association with the various co-morbidities and suggest that T therapy is necessary to improve health outcomes in men with TD., (Copyright © 2014 Elsevier Ltd. 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.)

Context: Androgen modulation of erectile function (EF) is widely accepted. However, the use of testosterone replacement therapy (TRT) in men with erectile dysfunction (ED) has generated an unprecedented debate., Objective: To summarize the relevant data on the incidence, diagnosis, and management of ED coexisting with hypogonadism and to develop a pathophysiology-based treatment algorithm., Evidence Acquisition: We reviewed the relevant medical literature, with a particular emphasis on original molecular studies, prospective observational data, and randomized controlled trials performed in the past 20 yr., Evidence Synthesis: Testosterone modulates nearly every component involved in EF, from pelvic ganglions to smooth muscle and the endothelial cells of the corpora cavernosa. It also regulates the timing of the erectile process as a function of sexual desire, coordinating penile erection with sex. Epidemiologic studies confirm the significant overlap of hypogonadism and ED; however, most guidelines do not consider the differential diagnosis of hypogonadism or the relevance of subclinical disease. Various clinical tools can help the physician to assess and restore androgen levels in men with ED. Special attention is given to fertility-sparing treatments, due to the increasing number of older men desiring fatherhood. The simultaneous use of phosphodiesterase type 5 inhibitors (PDE5-Is) and TRT has recently been questioned. Originally proposed as a salvage therapy for nonresponders to PDE5-Is, this approach has been inappropriately transformed into a combination therapy. Clinical data are consistent when reinterpreted in the proper framework, whereas molecular evidence remains controversial., Conclusions: A body of molecular and clinical evidence supports the use of TRT in hypogonadal patients with ED, although the benefit-risk ratio is uncertain in advanced age. Critical appraisal of this evidence enabled the development of a pathophysiology-oriented algorithm designed to avoid inappropriate treatments and support whether to start with TRT, PDE5-I only, or both. Apparently divergent findings are reconciled when TRT is correctly indicated. An improved diagnosis and individualized management is desirable in light of the many available options., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: Calculated free testosterone (cFT) is determined from total testosterone (TT), sex hormone binding globulin (SHBG), and albumin (Alb) levels using mathematical formulae. Variations in cFT due to changes in SHBG or Alb have not been investigated. We evaluated potential cFT variances determined with fixed Alb (4.3 g/dL) and measured Alb, and the point at which low SHBG and Alb combinations produced significant cFT variance., Method: We analyzed 11,176 data points from 5,797 men. cFT values with fixed versus actual Alb values were evaluated and compared. cFT levels were theoretically determined for all possible combinations of TT, SHBG, and Alb (8,343,552 combinations). Agreement between the 2 measures was assessed with Lin's concordance coefficient., Results: Mean Alb was 4.06 ± 0.32 g/dL. Mean SHBG was 39.0 ± 23.6 nmol/L. A fixed Alb of 4.3 g/dL did not produce significant variance for most cFT evaluations. Accuracy decreased when Alb was ≤3.5 g/dL in combination with SHBG ≤30 nmol/L, and this occurred in 1.2% of all data points., Conclusion: A fixed Alb of 4.3 g/dL is acceptable for most clinical evaluations. If Alb is ≤3.5 g/dL and SHBG is ≤30 nmol/L, the variance increases, and a free testosterone (FT) measurement by equilibrium dialysis is warranted for better accuracy.

Introduction: The role of estrogens in male sexual function and the pathogenesis of testosterone deficiency remain controversial and poorly understood., Aims: To review the distribution of estrogens in normal and testosterone deficient men, their potential role in sexual function, and the clinical implications of elevated estrogens during testosterone therapy., Methods: A comprehensive, broad-based literature review was conducted on the role of estrogens in male sexual function and testosterone deficiency., Results: Estrogens elicit a variety of physiological responses in men and may contribute to modulation of sexual function. In the absence of testosterone deficiency, elevations in estrogens do not appear to be harmful and estrogens may help maintain some, but not all, sexual function in castrated men. While the therapeutic use of estrogens at pharmacologic doses has been used to suppress serum testosterone, naturally occurring elevations of estrogens do not appear to be a cause of low testosterone. During testosterone replacement, estrogens may rise and occasionally reach elevated levels. There is a lack of evidence that treatment of elevated estrogen levels during testosterone replacement has benefit in terms of male sexuality., Conclusion: Further research on the importance of estrogens in male sexual function is needed. Current evidence does not support a role of naturally occurring estrogen elevations in testosterone deficiency or the treatment of elevated estrogens during testosterone therapy., (© 2012 International Society for Sexual Medicine.)

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 role of sex steroid hormones in modulating vascular function in men is of great importance, given that androgen deficiency is strongly associated with common medical conditions including metabolic syndrome, obesity, diabetes, hypertension and atherosclerosis. Testosterone deficiency afflicts approximately 30% of men ages 40-79 years. Testosterone replacement in deficient men with such co-morbidities ameliorates or partially reverses their progression. Studies in animal and humans suggest that androgen deficiency is associated with increased triglycerides (TGs), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C). Emerging evidence indicates that androgens may provide a protective effect against the development and/or progression of atherosclerosis in men., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Introduction: The safety of long-term physiological doses of testosterone (T) therapy in women with sexual dysfunction is a contentious issue, in part, because of fear of adverse effects, such as breast cancer, vascular disease, and excessive virilization. This unsubstantiated fear has hampered progress in treating women with sexual dysfunction using T therapy in physiological doses to achieve circulating levels in the normal range., Aim: To examine evidence derived from studies in female-to-male transsexuals (FMT) treated with supraphysiological (pharmacological) doses of T for long periods of time with no apparent major adverse effects., Methods: A comprehensive literature search of relevant articles published between 1980 and 2010 pertaining to the topic of T in FMTs was performed using PubMed. The following key words were used: female-to-male transsexuals; testosterone; virilization; gender re-assignment; and androgen therapy in women. Relevant articles were retrieved, reviewed, and the information was analyzed and evaluated for study methodology and major findings., Main Outcome Measures: Data from peer-reviewed publications were critically analyzed and the information was summarized., Results: The data from the studies reported in the literature to date strongly suggest that treatment of FMTs with supra-physiological doses of T had minimal adverse effects. No increase in mortality, breast cancer, vascular disease, or other major health problems were reported., Conclusions: No significant serious adverse effects were reported in FMTs treated with pharmacological doses of T. In light of the findings with supraphysiological doses of T, we suggest that treatment with T at doses producing physiological levels in women with sexual dysfunction are expected to produce limited and minimal adverse effects., (© 2010 International Society for Sexual Medicine.)

A considerable body of evidence exists suggesting that androgen deficiency contributes to the onset, progression, or both of cardiovascular disease (CVD). The aim of this review is to evaluate the relationships between testosterone (T) deficiency and risk factors of CVD and to discuss the implications of androgen deficiency in men with cardiovascular risk factors. The relationship between androgen deficiency and endothelial function, lipid profiles, inflammatory responses, altered vascular smooth muscle reactivity, and hypertension are discussed with regard to CVD. A comprehensive literature search was carried out with the use of Pub Med from 1980 through 2009, and relevant articles pertinent to androgen deficiency and vascular disease were evaluated and discussed. Low T, whether attributed to hypogonadism or androgen deprivation therapy, in men with prostate carcinoma, produces adverse effects on cardiovascular health. Androgen deficiency is associated with increased levels of total cholesterol, low-density lipoprotein, increased production of proinflammatory factors, and increased thickness of the arterial wall and contributes to endothelial dysfunction. Testosterone supplementation restores arterial vasoreactivity; reduces proinflammatory cytokines, total cholesterol, and triglyceride levels; and improves endothelial function but also might reduce high-density lipoprotein levels. Testosterone is an anabolic hormone with a wide range of beneficial effects on men's health. The therapeutic role of T in men's health, however, remains a hotly debated issue for a number of reasons, including the purported risk of prostate cancer. In view of the emerging evidence suggesting that androgen deficiency is a risk factor for CVD, androgen replacement therapy could potentially reduce CVD risk in hypogonadal men. It should be emphasized, however, that androgen replacement therapy should be done with very thorough and careful monitoring for prostate diseases.

Introduction: Although the term "medicalization" has been used by some to describe contemporary testosterone use in women with sexual disorders and testosterone deficiency syndrome, testosterone therapy for women with various gynecological and sexual disorders has been practiced since the late 1930s., Aim: The study aimed to perform a historical review of testosterone use in women with sexual and gynecological disorders. This review is necessary to bridge important knowledge gaps in the clinical use of testosterone in women with sexual health concerns and to provoke new thoughts and understanding of the multidisciplinary role of testosterone in women's overall health., Methods: Review of medical literature on androgen therapy in women was carried out from 1938 through 2008., Results: Approximately 70 years ago, clinicians from various disciplines relied on personal experience and clinical observations for outcome assessment of testosterone therapy in women. These early reports on testosterone use in women with sexual medical problems served as a foundation for the development of contemporary approaches and subsequent testosterone treatment regimens. Testosterone use was reported for sexual dysfunction, abnormal uterine bleeding, dysmenorrhea, menopausal symptoms, chronic mastitis and lactation, and benign and malignant tumors of the breast, uterus, and ovaries., Conclusions: Health-care professionals engaged in the management of women's health issues have observed the benefits of androgen therapy throughout much of the 20th century. Despite this clinical use of testosterone in women for more than seven decades, contemporary testosterone therapy in women is hotly debated, misunderstood, and often misrepresented in the medical community.

Context: The traditional belief that prostate cancer (PCa) growth is dependent on serum testosterone (T) level has been challenged by recent negative studies in noncastrated men., Objective: To provide an improved framework for understanding the relationship of PCa to serum T level that is consistent with current evidence and is based on established biochemical principles of androgen action within the prostate., Evidence Acquisition: A literature search was performed of publications dating from 1941 to 2008 that addressed experimental and clinical effects of androgens on prostate growth. Review of studies investigating the prostatic effects of manipulation of androgen concentrations in human and animal studies, and in PCa cell lines., Evidence Synthesis: Prostate growth is exquisitely sensitive to variations in androgen concentrations at very low concentrations, but becomes insensitive to changes in androgen concentrations at higher levels. This pattern is consistent with the observation that androgens exert their prostatic effects primarily via binding to the androgen receptor (AR), and that maximal androgen-AR binding is achieved at serum T concentrations well below the physiologic range. A Saturation Model is proposed that accounts for the seemingly contradictory results in human PCa studies. Changes in serum T concentrations below the point of maximal androgen-AR binding will elicit substantial changes in PCa growth, as seen with castration, or with T administration to previously castrated men. In contrast, once maximal androgen-AR binding is reached the presence of additional androgen produces little further effect., Conclusions: The evidence clearly indicates that there is a limit to the ability of androgens to stimulate PCa growth. A Saturation Model based on androgen-AR binding provides a satisfactory conceptual framework to account for the dramatic effects seen with castration as well as the minor impact of T administration in noncastrated men.

A considerable body of evidence exists suggesting a link among reduced testosterone plasma levels, type 2 diabetes (T2D), and insulin resistance (IR). Hypogonadal men are at higher risk for T2D. Here we evaluate the relationships between testosterone, metabolic syndrome (MetS), T2D, and IR and discuss the relationships among androgen deficiency and these factors, especially as it ultimately relates to the development of cardiovascular disease and erectile dysfunction (ED). Thus, a comprehensive literature search was carried out using PubMed, and relevant articles pertinent to androgen deficiency, T2D, IR, MetS, and ED were reviewed and discussed. Low testosterone precedes elevated fasting insulin, glucose, and hemoglobin A1c (HbA1C) values and may even predict the onset of diabetes. Treatment of prostate cancer patients with surgical or medical castration exacerbates IR and glycemic control, strengthening the link between testosterone deficiency and onset of T2D and IR. Androgen therapy of hypogonadal men improves insulin sensitivity, fasting glucose, and HbA1c levels. We suggest that androgen deficiency is associated with IR, T2D, MetS, and with increased deposition of visceral fat, which serves as an endocrine organ, producing inflammatory cytokines and thus promoting endothelial dysfunction and vascular disease.

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.

Background: Adverse side-effects of the glitazones have been frequently reported in both clinical and animal studies, especially with rosiglitazone (RGZ) and pioglitazone (PGZ), including congestive heart failure, osteoporosis, weight gain, oedema and anaemia. These led to consideration of an evidence-based hypothesis which would explain these diverse effects, and further suggested novel approaches by which this hypothesis could be tested., Presentation of Hypothesis: The literature on the clinical, metabolic and endocrine effects of glitazones in relation to the reported actions of testosterone in diabetes, metabolic syndrome, and cardiovascular disease is reviewed, and the following unifying hypothesis advanced: "Glitazones induce androgen deficiency in patients with Type 2 Diabetes Mellitus resulting in pathophysiological changes in multiple tissues and organs which may explain their observed clinical adverse effects." This also provides further evidence for the lipocentric concept of diabetes and its clinical implications., Testing of the Hypothesis: Clinical studies to investigate the endocrine profiles, including measurements of TT, DHT, SHBG, FT and estradiol, together with LH and FSH, in both men and women with T2DM before and after RGZ and PGZ treatment in placebo controlled groups, are necessary to provide data to substantiate this hypothesis. Also, studies on T treatment in diabetic men would further establish if the adverse effects of glitazones could be reversed or ameliorated by androgen therapy. Basic sciences investigations on the inhibition of androgen biosynthesis by glitazones are also warranted., Implications of the Hypothesis: Glitazones reduce androgen biosynthesis, increase their binding to SHBG, and attenuate androgen receptor activation, thus reducing the physiological actions of testosterone, causing relative and absolute androgen deficiency. This hypothesis explains the adverse effects of glitazones on the heart and other organs resulting from reversal of the action of androgens in directing the maturation of stem cells towards muscle, vascular endothelium, erythroid stem cells and osteoblasts, and away from adipocyte differentiation. The higher incidence of side-effects with RGZ than PGZ, may be explained by a detailed study of the mechanism by which glitazones down-regulate androgen biosynthesis and action, resulting in a state of androgen deficiency.

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.

Introduction: The mechanisms by which testosterone modulates female genital sexual arousal responses are poorly understood., Aim: To investigate the effects of testosterone on vaginal blood flow and the expression of estrogen and androgen receptor proteins in the rat vagina., Methods: Mature female Sprague-Dawley rats were sham-operated (intact) or ovariectomized. Fourteen days after ovariectomy, animals were continuously infused with vehicle or varying doses of testosterone (5.5-55 microg/day). After 2 weeks of treatment, vaginal blood flow in response to pelvic nerve stimulation was measured by laser Doppler flowmetry. Plasma levels of testosterone and estradiol were determined by radioimmunoassay and epithelial thickness was examined in fixed vaginal tissue sections. Androgen and estrogen receptor levels were assessed by equilibrium radioligand binding and by Western blot analyses., Results: Vaginal blood flow responses were significantly reduced in ovariectomized rats and normalized in animals infused with testosterone. Ovariectomy increased the expression of estrogen receptors and reduced the expression of androgen receptors with no change in receptor-ligand affinity. Testosterone increased the expression of both androgen and estrogen receptors in the vagina. While physiological (11 microg/day) and supraphysiological (55 microg/day) concentrations of testosterone normalized vaginal tissue weight, uterine tissue and whole body weights were not significantly different from ovariectomized rats infused with vehicle. Testosterone infusion, even at supraphysiological concentrations, did not change plasma estradiol levels when compared to vehicle-infused, ovariectomized rats. Likewise, the vaginal epithelium of testosterone-infused rats remained atrophic, similar to vehicle-infused, ovariectomized rats, indicating that testosterone is not aromatized to estrogens at significant levels in the vagina., Conclusions: Our data suggest that testosterone regulates androgen and estrogen receptor protein expression in the vagina and enhances vaginal perfusion by an androgen-dependent mechanism. We conclude that testosterone plays an important role in modulating the physiology of the vagina and contributes to improvement of genital sexual arousal responses.

Hypogonadism may play a significant role in the pathophysiology of erectile dysfunction (ED). A threshold level of testosterone may be necessary for normal erectile function. Testosterone replacement therapy is indicated in hypogonadal patients and is beneficial in patients with ED and hypogonadism. Monotherapy with testosterone for ED is of limited effectiveness and may be most promising in young patients with hypogonadism and without vascular risk factors for ED. A number of laboratory and human studies have shown the combination of testosterone and other ED treatments, such as phosphodiesterase type 5 (PDE5) inhibitors, to be beneficial in patients with ED and hypogonadism, who fail PDE5 inhibitor therapy alone. There is increasing evidence that combination therapy is effective in treating the symptoms of ED in patients for whom treatment failed with testosterone or PDE5 inhibitors alone. Testosterone replacement therapy has potentially evolved from a monotherapy for ED in cases of low testosterone, to a combination therapy with PDE5 inhibitors. Screening for hypogonadism may be useful in men with ED who fail prior PDE5 inhibitors, especially in populations at risk for hypogonadism such as type 2 diabetes and the metabolic syndrome.

Androgens play an important role in erectile function. However, the dose-response relationship between plasma testosterone levels and penile erection remains unclear. Intact (sham operated) or bilaterally orchiectomized, mature male Sprague-Dawley rats were used. Two weeks after surgery, rats were infused continuously with either vehicle (polyethyleneglycol) or varying doses of testosterone (44, 88, 220, or 440 mug/day) for 14 days using subcutaneous osmotic infusion pumps (study 1). In a separate study, 4 weeks after surgery, rats were infused with a lower range of testosterone doses (11, 22, or 44 mug/day) for 14 days (study 2). In the first study, intact rats had a mean plasma testosterone concentration of 0.56 +/- 0.12 ng/mL ( approximately 1.9 nM), as determined by standard radioimmunoassay. In the second study, a more sensitive enzyme-linked immunoassay was used to measure the lower testosterone levels. Using this assay, intact rats had a mean plasma testosterone concentration of 2.02 +/- 0.59 ng/mL. Intracavernosal pressure measurements indicated that orchiectomy resulted in a significant reduction in erectile function, when compared to intact animals, whereas testosterone infusion restored erectile function to varying degrees. Erectile function was maintained by a wide range of systemic testosterone levels as low as 10%-12% of normal physiological plasma concentrations. Below these concentrations, erectile function was significantly and positively correlated with testosterone plasma levels in a dose-dependent manner. Interestingly, prostate tissue mass was positively correlated to plasma testosterone levels across all concentrations examined. Protein expression of neural nitric oxide synthase (nNOS) and phosphodiesterase type 5 (PDE 5) was reduced in penile tissue from orchiectomized animals and increased in testosterone-infused animals, as assessed by Western blot analyses. We suggest that testosterone at levels approaching one-tenth normal physiological plasma concentration may represent a threshold value, below which erectile function declines in a dose-dependent fashion. However, different androgen-dependent tissues may exhibit varying sensitivities to circulating testosterone with regard to growth and function.

Ovarian steroids are known to be important in maintaining vaginal tissue, and evidence is mounting that imbalances in the hormonal milieu contribute to vaginal pathophysiology. To date, limited data are available on the effects of hormone deprivation and replacement on vaginal tissue morphology and vaginal innervation. The goal of this study was to assess the dynamic changes in vaginal tissue structure in response to sex steroid hormone deprivation and administration. Female Sprague-Dawley rats were either kept intact (controls) or ovariectomized. Ovariectomized animals were treated with vehicle, estradiol, testosterone, progesterone, or a combination of estradiol plus testosterone or progesterone. Histological techniques, including stereological analysis and immunohistochemistry for localization of neuronal markers, were used. Ovariectomy produced a significant decrease in epithelial height that was restored with estradiol replacement. Interestingly, a subphysiological dose of estradiol resulted in hyperplasia of the vaginal epithelium and nonvascular smooth muscle. Neither testosterone nor progesterone had a significant effect on epithelial height or muscularis thickness. However, testosterone treatment resulted in a significant increase in small adrenergic nerve fibers. Addition of either testosterone or progesterone to estradiol mitigated but did not abolish the effects of estradiol alone. This study demonstrates that estradiol and testosterone have differential effects on vaginal tissue parameters and that ovarian hormones are critical for the maintenance of genital tissue structure. Present observations also suggest that combined replacement regimens may be required for an optimal physiological response.

The role of steroid hormones in regulating vaginal smooth muscle contractility was investigated. Rabbits were kept intact or ovariectomized. After 2 weeks, animals were continuously infused with vehicle or supraphysiological levels of testosterone (100 microg/day), or estradiol (200 microg/day), for an additional 2 weeks. The distal vaginal tissue was used to assess contractility in organ baths and changes in tissue structure were assessed by histology. Ovariectomized animals infused with vehicle exhibited significant atrophy of the muscularis and decreased epithelial height, resulting in thinning of the vaginal wall. Estradiol infusion increased epithelial height, comparable to that of intact animals, but only partially restored the muscularis layer. In contrast, testosterone infusion completely restored the muscularis layer, but only partially restored the epithelial height. In vaginal tissue strips contracted with norepinephrine and treated with bretylium, electrical field stimulation (EFS) caused frequency-dependent relaxation that was slightly attenuated with vehicle, significantly inhibited with estradiol and significantly enhanced with testosterone. VIP-induced relaxation was slightly attenuated in tissues from vehicle and estradiol-infused groups, but was enhanced in tissues from testosterone-infused animals. Contraction elicited by EFS or exogenous norepinephrine was not significantly altered with ovariectomy or steroid hormone infusion when data were normalized to potassium contraction. However, the tissue from testosterone-infused animals developed significantly greater contractile force to norepinephrine. These observations suggest that steroid hormones may be important regulators of vaginal tissue structure and contractility.

We investigated, in a rabbit model, the effects of castration and testosterone replacement on: 1) the hemodynamics of the corpus cavernosum; 2) alpha-1 adrenergic receptor protein expression; 3) neural NO synthase protein expression and activity; 4) phosphodiesterase type 5 activity; and 5) trabecular smooth muscle/connective tissue balance. One week after bilateral orchiectomy, animals were treated for 7 days with vehicle alone, testosterone, or estradiol. Intact control animals received vehicle only. Systemic arterial blood and intracavernosal pressures (ICP) were measured in each animal before and after electrical stimulation of the cavernosal nerve. Alpha1-adrenergic receptor protein expression was determined by ligand binding studies. NO synthase expression and activity were determined by Western blot analyses and conversion of L-arginine to citrulline, respectively. Phosphodiesterase type 5 activity was determined by hydrolysis of guanosine 3',5'-cyclic monophosphate (cGMP) in tissue extracts in the absence or presence of 100 nM sildenafil. Smooth muscle content was assessed by Masson's trichrome staining and computer-assisted histomorphometry. Castration significantly reduced ICP, but it did not alter systemic arterial blood pressure during stimulation of the cavernosal nerve. Testosterone, but not estradiol, treatment prevented the effects of castration and restored ICP to values similar to those obtained in intact animals. Castration reduced expression of alpha1-adrenergic receptor, and this reduction was prevented or reversed by testosterone replacement. Neural NO synthase protein expression and total activity were not altered significantly by castration or after testosterone replacement. However, phosphodiesterase type 5 activity increased in castrated animals treated with testosterone. Castration significantly reduced trabecular smooth muscle content, and this reduction was restored by testosterone (but not estradiol) treatment. The results of this study demonstrate that androgen deprivation alters the functional responses and structure of erectile tissue.

Previous studies have indicated a greater incidence of atherosclerotic cardiovascular disease in men than in women of child-bearing age, suggesting that vascular interactions with sex steroids may effect pathogenesis in these cases. In the present study, it was found that the presence of 10-100 nM-testosterone in the growth medium of calf aortic smooth-muscle cells in culture stimulates lysyl oxidase activity approx. 2.5-fold in the medium and 5.5-fold in the fraction bound to the cell layer. Androgen receptors were identified in these cultured smooth-muscle cells, and their properties were very similar to those in the cytosolic fraction of whole bovine aortic tissue. These receptors appeared to be specific for androgen, of high affinity (Kd = 0.4 nM) and of low capacity (9000 sites/cell). The present results indicate that the aortic smooth-muscle cell is a cellular target for androgens, and thus raise the possibility that the development of fibrotic arterial lesions involving the deposition of excess collagen may in part be regulated by androgen-mediated stimulation of collagen cross-linkage formation as catalysed by lysyl oxidase.