madman
Super Moderator
Abstract
Testosterone, the main endogenous active androgen, is used to treat many clinical conditions, such as hypogonadism, infertility, erectile dysfunction, osteoporosis, anemia, and in transgender therapy (female-to-male transsexuals). Androgens are also used by athletes to enhance performance and endurance, and by non athlete weightlifters or bodybuilders to enhance muscle development and strength. Accordingly, testosterone and other anabolic-androgenic steroids are the main class of appearance and performance enhancing drugs (APEDs), i.e., substances used to improve appearance by building muscle mass or to enhance athletic performance.
Testosterone and other androgens, mainly at supraphysiological levels, affect every single body tissue or system, including the cardiovascular system. Testosterone increases cardiovascular disease risk, causes myocardial infarction, stroke, high blood pressure, blood clots, and heart failure. Among the potential mechanisms whereby testosterone affects the cardiovascular system, both indirect and direct actions have been reported. Indirect actions of testosterone on the cardiovascular system include changes in the lipid profile, insulin sensitivity, and hemostatic mechanisms, modulation of the sympathetic nervous system and renin-angiotensin-aldosterone system. Direct actions of testosterone in the cardiovascular system involves activation of proinflammatory and redox processes,decreased nitric oxide (NO) bioavailability, and stimulation of vasoconstrictor signaling pathways.
This chapter focuses on the effects of androgens, mainly testosterone, on the vascular system. The effects of testosterone on endothelial and vascular smooth muscle cells, as well as mechanisms involved in the effects of testosterone will be reviewed. Effects of testosterone on the perivascular adipose tissue, the immune, sympathetic, and renin-angiotensin systems will also be mentioned.
Stating the Problem
*Misuses or Non-prescribed Uses of Testosterone and Androgens
Testosterone and the Cardiovascular System
Although both supraphysiological and sub physiological levels of testosterone are associated with increased cardiovascular risk, the effects of supraphysiological levels of testosterone have been surprisingly little studied. Several reports indicate that supraphysiological levels of testosterone affect the function and structure of the cardiovascular system.
Among the potential mechanisms whereby testosterone affects the cardiovascular system, both indirect and direct actions have been reported. Indirect actions of testosterone on the cardiovascular system include changes in the lipid profile [increasing low-density lipoprotein (LDL) levels and decreasing high-density lipoprotein (HDL) levels], insulin sensitivity, and hemostatic mechanisms, modulation of the sympathetic nervous system and renin-angiotensin-aldosterone system. Direct actions of testosterone in the cardiovascular system involves activation of proinflammatory and redox processes, decreased nitric oxide (NO) bioavailability, and stimulation of vasoconstrictor signaling pathways (Bahrke et al. 1992; Farhat et al.1995; Hutchison et al. 1997; Bhasin et al. 2001; Urhausen et al. 2004; Palatini et al.1996; Santamarina et al. 2008; Vanberg and Atar 2010; El Scheich et al. 2013;Herring et al. 2013; Pope et al. 2014; Tostes et al. 2016; Baggish et al. 2017).
Testosterone affects many cardiac functions and consequently myocardial performance. Testosterone affects calcium (Ca2+) homeostasis, expression of alpha and beta adrenergic receptors, inotropic, chronotropic, and dromotropic responses, growth and hypertrophic responses, as recently reviewed (Pirompol et al. 2016; DeSmet et al. 2017; Elagizi et al. 2018; Ribeiro Júnior et al. 2018; Bianchi 2018;Carbajal-García et al. 2020)
Testosterone also affects the vasculature by interfering with mechanisms that control vascular function (relaxation and contraction) and structure (plasticity,growth, and remodeling). Vascular function is mainly determined by factors released from nerve terminals (norepinephrine from the sympathetic nervous system), endothelial cells (ECs), cells from the perivascular adipose tissue (PVAT), from resident and infiltrated immune cells (cytokines and chemokines), blood cells (eosinophils,platelets), and by the intrinsic components of the vascular smooth muscle cells (VSMCs, ion channels, receptors, enzymes, protein exchangers, and structural proteins).
Here we focus on the effects of androgens, mainly testosterone, on the vascular system. The effects of testosterone on ECs and VSMCs will be discussed. Testosterone effects in the PVAT and other mechanisms that control vascular function will also be addressed. The mechanisms involved in the effects of testosterone in these cells and tissues will be reviewed (Fig. 1).
Vascular Effects of Testosterone
Impact of Testosterone on Endothelial Cells
The vascular endothelium is a monolayer of cells between the blood vessel lumen and VSMCs. Vascular ECs, a key cellular component of blood vessels, play important roles in vascular health and disease (Vanhoutte et al. 2017). Endothelial cells contain functional androgen receptor (AR) and are targets for androgens’ action. As will be discussed, some androgen’s effects rely on AR activation, while others occur independently of AR-molecular pathways (Nheu et al. 2011).
Impact of Testosterone on Vascular Smooth Muscle Cells
Not only ECs but also VSMCs contain functional AR and are targets for androgensactions. Biological activities of androgens in VSMCs are predominantly mediated through the AR, but many AR-independent effects also exist. AR-mediated effects involve transcriptional control of target genes while AR-independent effects usually involve androgens activation of multiple signaling pathways.
The complexity of testosterone effects is evident, and further studies are required for a better understanding of the pro- or anti-oxidative/apoptotic effects of testosterone, especially in the cardiovascular system.
Impact of Testosterone on the Perivascular Adipose Tissue Other Mechanisms That Control Vascular Function
Until recently, the adipose tissue was considered as only being involved in total body lipid and energy homeostasis. However, nowadays it is well known that adipose tissue also exerts major endocrine and paracrine effects via the release of various inflammatory adipokines and other factors that affect vascular tone (Maenhaut and Van de Voorde 2011).
Androgens increase vascular resistance and blood pressure in humans. In addition, increased resting muscle sympathetic nerve activity and lower forearm blood flow are observed in young men who use anabolic androgenic steroids. Androgens users also exhibit increased heart rate during strength training and increased muscle sympathetic nerve activity and lower forearm blood flow in response to mental stress, indicating that androgens exacerbate neurovascular control throughout stress reactions (Alves et al. 2010; Porello et al. 2018). The increased blood pressure and augmented sympathetic outflow in androgens’ users may increase cardiovascular disease risk in humans.
Applications to Other Areas of Public Health
Testosterone, the main endogenous active androgen, is used to treat many clinical conditions, such as hypogonadism, infertility, erectile dysfunction, osteoporosis, anemia, and in transgender therapy (female-to-male transsexuals). Androgens are also used by athletes to enhance performance and endurance, and by non athlete weightlifters or bodybuilders to enhance muscle development and strength. Accordingly, testosterone and other anabolic-androgenic steroids are the main class of appearance and performance enhancing drugs (APEDs), i.e., substances used to improve appearance by building muscle mass or to enhance athletic performance.
Testosterone and other androgens, mainly at supraphysiological levels, affect every single body tissue or system, including the cardiovascular system. Testosterone increases cardiovascular disease risk, causes myocardial infarction, stroke, high blood pressure, blood clots, and heart failure. Among the potential mechanisms whereby testosterone affects the cardiovascular system, both indirect and direct actions have been reported. Indirect actions of testosterone on the cardiovascular system include changes in the lipid profile, insulin sensitivity, and hemostatic mechanisms, modulation of the sympathetic nervous system and renin-angiotensin-aldosterone system. Direct actions of testosterone in the cardiovascular system involves activation of proinflammatory and redox processes,decreased nitric oxide (NO) bioavailability, and stimulation of vasoconstrictor signaling pathways.
This chapter focuses on the effects of androgens, mainly testosterone, on the vascular system. The effects of testosterone on endothelial and vascular smooth muscle cells, as well as mechanisms involved in the effects of testosterone will be reviewed. Effects of testosterone on the perivascular adipose tissue, the immune, sympathetic, and renin-angiotensin systems will also be mentioned.
Stating the Problem
*Misuses or Non-prescribed Uses of Testosterone and Androgens
Testosterone and the Cardiovascular System
Although both supraphysiological and sub physiological levels of testosterone are associated with increased cardiovascular risk, the effects of supraphysiological levels of testosterone have been surprisingly little studied. Several reports indicate that supraphysiological levels of testosterone affect the function and structure of the cardiovascular system.
Among the potential mechanisms whereby testosterone affects the cardiovascular system, both indirect and direct actions have been reported. Indirect actions of testosterone on the cardiovascular system include changes in the lipid profile [increasing low-density lipoprotein (LDL) levels and decreasing high-density lipoprotein (HDL) levels], insulin sensitivity, and hemostatic mechanisms, modulation of the sympathetic nervous system and renin-angiotensin-aldosterone system. Direct actions of testosterone in the cardiovascular system involves activation of proinflammatory and redox processes, decreased nitric oxide (NO) bioavailability, and stimulation of vasoconstrictor signaling pathways (Bahrke et al. 1992; Farhat et al.1995; Hutchison et al. 1997; Bhasin et al. 2001; Urhausen et al. 2004; Palatini et al.1996; Santamarina et al. 2008; Vanberg and Atar 2010; El Scheich et al. 2013;Herring et al. 2013; Pope et al. 2014; Tostes et al. 2016; Baggish et al. 2017).
Testosterone affects many cardiac functions and consequently myocardial performance. Testosterone affects calcium (Ca2+) homeostasis, expression of alpha and beta adrenergic receptors, inotropic, chronotropic, and dromotropic responses, growth and hypertrophic responses, as recently reviewed (Pirompol et al. 2016; DeSmet et al. 2017; Elagizi et al. 2018; Ribeiro Júnior et al. 2018; Bianchi 2018;Carbajal-García et al. 2020)
Testosterone also affects the vasculature by interfering with mechanisms that control vascular function (relaxation and contraction) and structure (plasticity,growth, and remodeling). Vascular function is mainly determined by factors released from nerve terminals (norepinephrine from the sympathetic nervous system), endothelial cells (ECs), cells from the perivascular adipose tissue (PVAT), from resident and infiltrated immune cells (cytokines and chemokines), blood cells (eosinophils,platelets), and by the intrinsic components of the vascular smooth muscle cells (VSMCs, ion channels, receptors, enzymes, protein exchangers, and structural proteins).
Here we focus on the effects of androgens, mainly testosterone, on the vascular system. The effects of testosterone on ECs and VSMCs will be discussed. Testosterone effects in the PVAT and other mechanisms that control vascular function will also be addressed. The mechanisms involved in the effects of testosterone in these cells and tissues will be reviewed (Fig. 1).
Vascular Effects of Testosterone
Impact of Testosterone on Endothelial Cells
The vascular endothelium is a monolayer of cells between the blood vessel lumen and VSMCs. Vascular ECs, a key cellular component of blood vessels, play important roles in vascular health and disease (Vanhoutte et al. 2017). Endothelial cells contain functional androgen receptor (AR) and are targets for androgens’ action. As will be discussed, some androgen’s effects rely on AR activation, while others occur independently of AR-molecular pathways (Nheu et al. 2011).
Impact of Testosterone on Vascular Smooth Muscle Cells
Not only ECs but also VSMCs contain functional AR and are targets for androgensactions. Biological activities of androgens in VSMCs are predominantly mediated through the AR, but many AR-independent effects also exist. AR-mediated effects involve transcriptional control of target genes while AR-independent effects usually involve androgens activation of multiple signaling pathways.
The complexity of testosterone effects is evident, and further studies are required for a better understanding of the pro- or anti-oxidative/apoptotic effects of testosterone, especially in the cardiovascular system.
Impact of Testosterone on the Perivascular Adipose Tissue Other Mechanisms That Control Vascular Function
Until recently, the adipose tissue was considered as only being involved in total body lipid and energy homeostasis. However, nowadays it is well known that adipose tissue also exerts major endocrine and paracrine effects via the release of various inflammatory adipokines and other factors that affect vascular tone (Maenhaut and Van de Voorde 2011).
Androgens increase vascular resistance and blood pressure in humans. In addition, increased resting muscle sympathetic nerve activity and lower forearm blood flow are observed in young men who use anabolic androgenic steroids. Androgens users also exhibit increased heart rate during strength training and increased muscle sympathetic nerve activity and lower forearm blood flow in response to mental stress, indicating that androgens exacerbate neurovascular control throughout stress reactions (Alves et al. 2010; Porello et al. 2018). The increased blood pressure and augmented sympathetic outflow in androgens’ users may increase cardiovascular disease risk in humans.
Applications to Other Areas of Public Health
