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International Journal of Impotence... Nov 2022The use of testosterone therapy has a complex history of apprehension and questions regarding its safety. Despite an eventual consensus that testosterone therapy was... (Review)
Review
The use of testosterone therapy has a complex history of apprehension and questions regarding its safety. Despite an eventual consensus that testosterone therapy was safe and effective, several studies relating to cardiovascular risks emerged in the last decade, rekindling skepticism regarding the safety of testosterone therapy. Given the utility of testosterone therapy in treating the symptoms of hypogonadism, it remains crucial to closely examine the safety of testosterone therapy. The present article synthesizes the current evidence regarding cardiovascular risks that may be associated with testosterone therapy, the potential mechanisms regarding testosterone's efficacy, and future directions in evaluating the safety of its use.
Topics: Humans; Cardiovascular Diseases; Hormone Replacement Therapy; Hypogonadism; Testosterone
PubMed: 34999717
DOI: 10.1038/s41443-021-00516-6 -
Frontiers in Neuroendocrinology Jan 2014Compelling evidence exists for pervasive sex differences in pathological conditions, including anxiety and depressive disorders, with females more than twice as likely... (Review)
Review
Compelling evidence exists for pervasive sex differences in pathological conditions, including anxiety and depressive disorders, with females more than twice as likely to be afflicted. Gonadal hormones may be a major factor in this disparity, given that women are more likely to experience mood disturbances during times of hormonal flux, and testosterone may have protective benefits against anxiety and depression. In this review we focus on the effects of testosterone in males and females, revealed in both human and animal studies. We also present possible neurobiological mechanisms underlying testosterone's mostly protective benefits, including the brain regions, neural circuits, and cellular and molecular pathways involved. While the precise underlying mechanisms remain unclear, both activational and organizational effects of testosterone appear to contribute to these effects. Future clinical studies are necessary in order to better understand when and how testosterone therapy may be effective in both sexes.
Topics: Animals; Anxiety; Depression; Female; Humans; Male; Sex Characteristics; Signal Transduction; Testosterone
PubMed: 24076484
DOI: 10.1016/j.yfrne.2013.09.001 -
Endocrine Reviews Aug 2017In the circulation, testosterone and other sex hormones are bound to binding proteins, which play an important role in regulating their transport, distribution,... (Review)
Review
In the circulation, testosterone and other sex hormones are bound to binding proteins, which play an important role in regulating their transport, distribution, metabolism, and biological activity. According to the free hormone hypothesis, which has been debated extensively, only the unbound or free fraction is biologically active in target tissues. Consequently, accurate determination of the partitioning of testosterone between bound and free fractions is central to our understanding of how its delivery to the target tissues and biological activity are regulated and consequently to the diagnosis and treatment of androgen disorders in men and women. Here, we present a historical perspective on the evolution of our understanding of the binding of testosterone to circulating binding proteins. On the basis of an appraisal of the literature as well as experimental data, we show that the assumptions of stoichiometry, binding dynamics, and the affinity of the prevailing models of testosterone binding to sex hormone-binding globulin and human serum albumin are not supported by published experimental data and are most likely inaccurate. This review offers some guiding principles for the application of free testosterone measurements in the diagnosis and treatment of patients with androgen disorders. The growing number of testosterone prescriptions and widely recognized problems with the direct measurement as well as the computation of free testosterone concentrations render this critical review timely and clinically relevant.
Topics: Humans; Serum Albumin, Human; Sex Hormone-Binding Globulin; Testosterone; Transcortin
PubMed: 28673039
DOI: 10.1210/er.2017-00025 -
Sexual Medicine Reviews Apr 2020Testosterone therapy has been controversial since its synthesis in the 1930s to the present day. Testosterone's history provides depth and context for current... (Review)
Review
INTRODUCTION
Testosterone therapy has been controversial since its synthesis in the 1930s to the present day. Testosterone's history provides depth and context for current controversies.
AIM
To review the history of testosterone therapy from its initial synthesis in the 1930s to the modern day.
METHODS
Expert review of the literature.
MAIN OUTCOME MEASURES
Impactful events in the history of testosterone.
RESULTS
By the 1940s there was already a fascinating literature that described the many symptomatic benefits of testosterone therapy that are recognized today. Numerous early reports suggested testosterone therapy improved angina pectoris and peripheral vascular disease. The assertion by Huggins and Hodges (Cancer Res 1941;1:293-297) in 1941 that testosterone activated prostate cancer (PCa) cast a pall for the next 70 years. The introduction of the radioimmunoassay in the 1970s shifted the diagnosis of testosterone deficiency from signs and symptoms to an undue emphasis on blood test results. The fear of PCa was the primary obstacle to the adoption of testosterone therapy for decades. Prescription rates increased as accumulated evidence showed testosterone therapy was not associated with increased PCa risks. The observation that androgenic stimulation of PCa reaches a maximum at relatively low testosterone concentrations-the saturation model-provided the theoretical framework for understanding the relation between androgens and PCa and led to multiple case series documenting reassuring results of testosterone therapy in men with PCa. Recent concerns regarding cardiovascular risks also have diminished because new evidence suggests testosterone therapy might actually be cardioprotective. In 2016 the Testosterone Trials provided high-quality evidence of multiple benefits of testosterone therapy, nearly all of which had been recognized by clinicians by 1940.
CONCLUSIONS
If the past has any lessons for the future, it is likely that research will continue to demonstrate health benefits of testosterone therapy, while it remains one of the most controversial topics in medicine. Morgentaler A, Traish A. The History of Testosterone and the Evolution of its Therapeutic Potential. Sex Med Rev 2020;8:286-296.
Topics: Androgens; Angina Pectoris; History, 20th Century; History, 21st Century; Humans; Male; Peripheral Vascular Diseases; Prostatic Neoplasms; Testosterone
PubMed: 29661690
DOI: 10.1016/j.sxmr.2018.03.002 -
Reviews in the Neurosciences Apr 2023Neuroplasticity or neural plasticity implicates the adaptive potential of the brain in response to extrinsic and intrinsic stimuli. The concept has been utilized in... (Review)
Review
Neuroplasticity or neural plasticity implicates the adaptive potential of the brain in response to extrinsic and intrinsic stimuli. The concept has been utilized in different contexts such as injury and neurological disease. Neuroplasticity mechanisms have been classified into neuroregenerative and function-restoring processes. In the context of injury, neuroplasticity has been defined in three post-injury epochs. Testosterone plays a key yet double-edged role in the regulation of several neuroplasticity alterations. Research has shown that testosterone levels are affected by numerous factors such as age, stress, surgical procedures on gonads, and pharmacological treatments. There is an ongoing debate for testosterone replacement therapy (TRT) in aging men; however, TRT is more useful in young individuals with testosterone deficit and more specific subgroups with cognitive dysfunction. Therefore, it is important to pay early attention to testosterone profile and precisely uncover its harms and benefits. In the present review, we discuss the influence of environmental factors, aging, and gender on testosterone-associated alterations in neuroplasticity, as well as the two-sided actions of testosterone in the nervous system. Finally, we provide practical insights for further study of pharmacological treatments for hormonal disorders focusing on restoring neuroplasticity.
Topics: Male; Humans; Testosterone; Aging; Brain; Nervous System Diseases; Neuronal Plasticity
PubMed: 36017670
DOI: 10.1515/revneuro-2022-0033 -
The Journal of Clinical Endocrinology... Feb 2017Findings of studies of testosterone's effects on muscle strength and physical function in older men have been inconsistent; its effects on muscle power and fatigability... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Findings of studies of testosterone's effects on muscle strength and physical function in older men have been inconsistent; its effects on muscle power and fatigability have not been studied.
OBJECTIVE
To determine the effects of testosterone administration for 3 years in older men on muscle strength, power, fatigability, and physical function.
DESIGN, SETTING, AND PARTICIPANTS
This was a double-blind, placebo-controlled, randomized trial of healthy men ≥60 years old with total testosterone levels of 100 to 400 ng/dL or free testosterone levels <50 pg/mL.
INTERVENTIONS
Random assignment to 7.5 g of 1% testosterone or placebo gel daily for 3 years.
OUTCOME MEASURES
Loaded and unloaded stair-climbing power, muscle strength, power, and fatigability in leg press and chest press exercises, and lean mass at baseline, 6, 18, and 36 months.
RESULTS
The groups were similar at baseline. Testosterone administration for 3 years was associated with significantly greater performance in unloaded and loaded stair-climbing power than placebo (mean estimated between-group difference, 10.7 W [95% confidence interval (CI), -4.0 to 25.5], P = 0.026; and 22.4 W [95% CI, 4.6 to 40.3], P = 0.027), respectively. Changes in chest-press strength (estimated mean difference, 16.3 N; 95% CI, 5.5 to 27.1; P < 0.001) and power (mean difference 22.5 W; 95% CI, 7.5 to 37.5; P < 0.001), and leg-press power were significantly greater in men randomized to testosterone than in those randomized to placebo. Lean body mass significantly increased more in the testosterone group.
CONCLUSION
Compared with placebo, testosterone replacement in older men for 3 years was associated with modest but significantly greater improvements in stair-climbing power, muscle mass, and power. Clinical meaningfulness of these treatment effects and their impact on disability in older adults with functional limitations remains to be studied.
Topics: Aged; Aging; Body Composition; Body Mass Index; Double-Blind Method; Hormone Replacement Therapy; Humans; Male; Middle Aged; Muscle Strength; Muscle, Skeletal; Outcome Assessment, Health Care; Physical Fitness; Testosterone
PubMed: 27754805
DOI: 10.1210/jc.2016-2771 -
Drugs in R&D 2004Schering AG is developing a formulation of testosterone undecanoate [Nebido] for the treatment of testosterone deficiency or hypogonadism. This deficiency can lead to... (Review)
Review
Schering AG is developing a formulation of testosterone undecanoate [Nebido] for the treatment of testosterone deficiency or hypogonadism. This deficiency can lead to decreased muscle mass, impaired muscle function, osteoporosis, reduced sexual function and mental degeneration. Schering claims that its new formulation provides superior control of blood levels of the drug and permits a longer period of application. Nebido requires only four injections per year, and represents a major improvement for men with testosterone deficiency. Schering AG received approval of its testosterone undecanoate formulation in its first European country, Finland, in November 2003 for the treatment of hypogonadism in men. In July 2004, Schering's testosterone undecanoate formulation completed approval of the European mutual recognition procedure. This approval clears the way for marketing the product (as Nebido) in the large pharmaceutical markets like Germany, France and the UK. The initial phase of the product launch will occur in Finland in October 2004, and in Germany in November 2004. Other European countries will follow in 2005, and following receipt of approval, it will be introduced in the first Latin American and Asian countries. In its 2002 Annual Report, Schering predicted that testosterone undecanoate has the potential to reach peak sales of euro 100 million, 3 years after launch-launch in Europe was at the time anticipated in 2004.
Topics: Adult; Clinical Trials, Phase II as Topic; Humans; Hypogonadism; Male; Oligospermia; Testosterone
PubMed: 15563244
DOI: 10.2165/00126839-200405060-00012 -
MMW Fortschritte Der Medizin Nov 2020
Review
Topics: Androgens; Diabetes Mellitus, Type 2; Humans; Testosterone; Testosterone Congeners
PubMed: 33164195
DOI: 10.1007/s15006-020-4429-1 -
The Journal of Clinical Endocrinology... Jan 2024Few long-term randomized trials have evaluated the efficacy of testosterone replacement therapy (TRT) in improving sexual function and hypogonadal symptoms in men with... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Few long-term randomized trials have evaluated the efficacy of testosterone replacement therapy (TRT) in improving sexual function and hypogonadal symptoms in men with hypogonadism and whether effects are sustained beyond 12 months.
OBJECTIVE
The Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study evaluated the effect of TRT on major adverse cardiovascular events in middle-aged and older men with hypogonadism. The Sexual Function Study, nested within the parent trial, determined testosterone's efficacy in improving sexual activity, hypogonadal symptoms, libido, and erectile function among men reporting low libido.
METHODS
Among 5204 men, 45-80 years, with 2 testosterone concentrations <300 ng/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk enrolled in the TRAVERSE trial, 1161 with low libido were enrolled in the Sexual Function Study (587 randomized to receive 1.62% testosterone gel and 574 to placebo gel for the duration of their participation in the study). Primary outcome was change from baseline in sexual activity score. Secondary outcomes included hypogonadal symptoms, erectile function, and sexual desire.
RESULTS
TRT was associated with significantly greater improvement in sexual activity than placebo (estimated mean [95% CI] between-group difference 0.49 [0.19,0.79] and 0.47 [0.11, 0.83] acts per day at 6 and 12 months, respectively; omnibus test P = .011); treatment effect was maintained at 24 months. TRT improved hypogonadal symptoms and sexual desire, but not erectile function, compared with placebo.
CONCLUSION
In middle-aged and older men with hypogonadism and low libido, TRT for 2 years improved sexual activity, hypogonadal symptoms, and sexual desire, but not erectile function.
Topics: Male; Middle Aged; Humans; Aged; Erectile Dysfunction; Sexual Behavior; Testosterone; Cardiovascular Diseases; Hypogonadism
PubMed: 37589949
DOI: 10.1210/clinem/dgad484 -
Molecules (Basel, Switzerland) Feb 2021Testosterone derivatives and related compounds (such as anabolic-androgenic steroids-AAS) are frequently misused by athletes (both professional and amateur) wishing to... (Review)
Review
Testosterone derivatives and related compounds (such as anabolic-androgenic steroids-AAS) are frequently misused by athletes (both professional and amateur) wishing to promote muscle development and strength or to cover AAS misuse. Even though these agents are vastly regarded as abusive material, they have important pharmacological activities that cannot be easily replaced by other drugs and have therapeutic potential in a range of conditions (e.g., wasting syndromes, severe burns, muscle and bone injuries, anemia, hereditary angioedema). Testosterone and related steroids have been in some countries treated as controlled substances, which may affect the availability of these agents for patients who need them for therapeutic reasons in a given country. Although these agents are currently regarded as rather older generation drugs and their use may lead to serious side-effects, they still have medicinal value as androgenic, anabolic, and even anti-androgenic agents. This review summarizes and revisits the medicinal use of compounds based on the structure and biological activity of testosterone, with examples of specific compounds. Additionally, some of the newer androgenic-anabolic compounds are discussed such as selective androgen receptor modulators, the efficacy/adverse-effect profiles of which have not been sufficiently established and which may pose a greater risk than conventional androgenic-anabolic agents.
Topics: Animals; Designer Drugs; Humans; Plants; Prodrugs; Steroids; Testosterone
PubMed: 33672087
DOI: 10.3390/molecules26041032