madman
Super Moderator
In men, 70% of circulating testosterone binds with high affinity to plasma sex hormone-binding globulin (SHBG), which determines its bioavailability in their target cells. In recent years, a growing body of evidence has shown that circulating SHBG not only is a passive carrier for steroid hormones but also actively regulates testosterone signaling through putative plasma membrane receptors and by local expression of androgen-binding proteins apparently to reach locally elevated testosterone concentrations in specific androgen target tissues. Circulating SHBG levels are influenced by metabolic and hormonal factors, and they are reduced in obesity and insulin resistance, suggesting that SHBG may have a broader clinical utility in assessing the risk for cardiovascular diseases. Importantly, plasma SHBG levels are strongly correlated with testosterone concentrations, and in men, low testosterone levels are associated with an adverse cardiometabolic profile. Although obesity and insulin resistance are associated with an increased incidence of cardiovascular disease, whether they lead to abnormal expression of circulating SHBG or its interaction with androgen signaling remains to be elucidated. SHBG is produced mainly in the liver, but it can also be expressed in several tissues including the brain, fat tissue, and myocardium. Expression of SHBG is controlled by peroxisome proliferator-activated receptor c (PPARc) and AMP-activated protein kinase (AMPK). AMPK/PPAR interaction is critical to regulating hepatocyte nuclear factor-4 (HNF4), a prerequisite for SHBG upregulation. In cardiomyocytes, testosterone activates AMPK and PPARs. (therefore, the description of local expression of cardiac SHBG and its circulating levels may shed new light to explain physiological and adverse cardiometabolic roles of androgens in different tissues. According to emerging clinical evidence, here, we will discuss the potential mechanisms with cardioprotective effects and SHBG levels to be used as an early metabolic and cardiovascular biomarker in men.
1. Introduction
The incidence of cardiovascular mortality is higher in men than in women [1–3], and gender differences are highly related to circulating plasma levels of sex-steroid hormones [4, 5]. Estrogens have cardioprotective effects in women prior to menopause, but in adult men, the main gender-related steroid hormone is testosterone [6]. A study from the Mayo Clinic (2018) exhaustively reviewed and analyzed the main clinical publications in the last 10 years related to plasma testosterone levels, testosterone administration therapies, and their impact on the cardiovascular system.
Evidence indicates that physiological testosterone levels are beneficial for the male cardiovascular system, while testosterone deficiency is associated with an unfavorable metabolic profile and increased cardiovascular risk [7].
Sex hormone-binding globulin (SHBG) transports testosterone within the bloodstream and regulates its bioavailability and access to extravascular target tissues [8, 9]. In men, plasma testosterone levels fluctuate throughout life and begin to decrease in middle age and continue to decline with age [4]. Low plasma testosterone levels in men have been associated with the concept of “andropause,” which rapidly has become a worldwide epidemic condition related to an adverse cardiometabolic risk profile [4, 10, 11]. There is substantial clinical evidence indicating that androgen signaling plays a key role in the cardioprotective benefits elicited by physiological testosterone levels in men.
Several cross-sectional and cohort studies have shown that low SHBG levels are associated with an increased risk of developing metabolic diseases [12, 13]. An association has also been described between SHBG actions unrelated to the transport of sex hormones and metabolic disorders. A meta-analysis examining different concentrations of SHBG showed that low levels of SHBG in men are a predictor of metabolic syndrome and type 2 diabetes [14]. Metabolic abnormalities are closely associated with cardiovascular disease [15–17]. Despite previous evidence, a recent cohort study including about 150,000 middle-aged and aged adult men (40–69 years old) concluded that low circulating SHBG levels are associated with diminished mortality in “all-cause” included in this study, particularly those related to cancer and cardiovascular diseases (CVDs). For total and calculated free testosterone, the expected inverse association with SHBG levels were observed only for “all-cause” and cancer mortality and not for CVD deaths [18]. Another cohort study showed, in a group with age ranging from 35 to 80 years, that elevated levels in SHBG were positively associated with increased incidental cardiovascular disease risk in men over 65 years [19]. However, it is still unknown whether changes in the circulating plasma levels of SHBG, the local expression of SHBG and androgen-binding proteins in tissues such as the heart, or the secondary effects of SHBG level fluctuations in free testosterone are responsible for these effects. In this review, we are going to discuss the mechanisms currently proposed for SHBG cardioprotective effects and how the use of circulating SHBG levels can be useful as an early metabolic and cardiovascular biomarker.
2. SHBG Is not Only a Passive Carrier for Sex-Steroids
In men, approximately 70% of circulating plasma testosterone binds with high affinity to circulating SHBG, 20–30% to albumin, and the remaining 1-2% circulates in free form [20]. In women, the majority of plasma estradiol and testosterone is bound to SHBG and other proteins and is not bioavailable; only about 2% of these sex hormones are free to bind to receptors and have an impact on the body [21]. Circulating SHBG modulates the level of free sex-steroid hormones that can enter diverse target cells [22]. The endocrinological concept is known as the “free hormone hypothesis” states that the “bioavailable” steroid hormone, i.e., the one that has an effect when bound to its receptor, is the unbound or “free” fraction of steroid hormones [23]. However, recent evidence indicates that circulating SHBG not only is a passive carrier of male sex hormones but also actively regulates testosterone uptake and androgen signaling [24]. Because circulating SHBG binds to sex hormones, the relative plasma levels of this protein can modulate the concentrations of sex-related hormones accessible for use by the body, which has an impact on the processes regulated by the sex hormones [25]. SHBG can also release hormones in specific tissues and cells directly, which can influence both production and effects of sex hormones as well as the expression and function of circulating SHBG. Also, sex hormones bound to circulating SHBG can change the affinity of SHBG to its peripheral receptors. Moreover, intracellular expression of SHBG in testicular proximal tubule cells increases the uptake of dihydrotestosterone and prolongs the expression of androgen-responsive genes [26].
2.1. Circulating SHBG Internalization
2.2. SHBG as an External Ligand
3. Signal Transduction Pathways Involved in SHBG Expression
SHBG is a glycoprotein synthesized and secreted by the liver [46–48] that transports sex-steroids (androgens and estrogens) from steroidogenic organs to their target tissues [6, 20, 24, 49, 50].
4. Effects of SHBG and Testosterone on Cardiac Function: Mechanistic Evidence from Animal and Human Research
Most of the research linking SHBG and androgens has been focused on their circulating levels. If altered levels of circulating SHBG are causally related to high cardiovascular risk, raises the question, what is the potential mechanism?
In humans, plasma SHBG levels are influenced by nutritional state, metabolism, and hormonal factors [9, 58, 96, 97].
*Physiological effects of testosterone in cardiac cells include handling of energy substrates and increased gene expression of key enzymes involved in glucose uptake and glycolysis; and regulation of critical transcription factors related to stimuli that affect cardiomyocyte function
5. Human Diseases and Medications Related to Circulating SHBG
Various human diseases have been associated with altered circulating levels of SHBG, many of which also are linked with high CVD risk (Table 1).
6. Conclusion and Future Research
Given the important roles of androgens in normal men's physiology, abnormal levels must be considered one of the main causes implicated in several disorders and pathological conditions [108, 144–146]. According to a 2017 update demography report from the American Heart Association, almost one in three adult men have some type of cardiovascular disease [147]. In the context of human disease relevance, the international expert consensus panel that convened in 2015 concluded that there is a need for a major research initiative to explore the possible cardioprotective benefits of testosterone therapy, implying that there is sufficient evidence regarding the safety of testosterone therapy in hypogonadal men and that the direction of future research should be set toward defining suitable therapeutic options for cardiovascular disease [148, 149]. Research in the field of androgen signaling will provide a considerable understanding of the physiological and pathological roles of SHBG and sex-steroid hormones. Thus, an appropriate description of testosterone signaling considering circulating and cardiac SHBG expression might help explain both physiological and adverse cardiac metabolic roles of androgens (particularly androgen deficiency). Research directed to elucidate whether plasmatic and cardiac SHBG expression is associated with physiological testosterone levels could represent novel research approaches to study insulin resistance, obesity, diabetes, and heart failure.
1. Introduction
The incidence of cardiovascular mortality is higher in men than in women [1–3], and gender differences are highly related to circulating plasma levels of sex-steroid hormones [4, 5]. Estrogens have cardioprotective effects in women prior to menopause, but in adult men, the main gender-related steroid hormone is testosterone [6]. A study from the Mayo Clinic (2018) exhaustively reviewed and analyzed the main clinical publications in the last 10 years related to plasma testosterone levels, testosterone administration therapies, and their impact on the cardiovascular system.
Evidence indicates that physiological testosterone levels are beneficial for the male cardiovascular system, while testosterone deficiency is associated with an unfavorable metabolic profile and increased cardiovascular risk [7].
Sex hormone-binding globulin (SHBG) transports testosterone within the bloodstream and regulates its bioavailability and access to extravascular target tissues [8, 9]. In men, plasma testosterone levels fluctuate throughout life and begin to decrease in middle age and continue to decline with age [4]. Low plasma testosterone levels in men have been associated with the concept of “andropause,” which rapidly has become a worldwide epidemic condition related to an adverse cardiometabolic risk profile [4, 10, 11]. There is substantial clinical evidence indicating that androgen signaling plays a key role in the cardioprotective benefits elicited by physiological testosterone levels in men.
Several cross-sectional and cohort studies have shown that low SHBG levels are associated with an increased risk of developing metabolic diseases [12, 13]. An association has also been described between SHBG actions unrelated to the transport of sex hormones and metabolic disorders. A meta-analysis examining different concentrations of SHBG showed that low levels of SHBG in men are a predictor of metabolic syndrome and type 2 diabetes [14]. Metabolic abnormalities are closely associated with cardiovascular disease [15–17]. Despite previous evidence, a recent cohort study including about 150,000 middle-aged and aged adult men (40–69 years old) concluded that low circulating SHBG levels are associated with diminished mortality in “all-cause” included in this study, particularly those related to cancer and cardiovascular diseases (CVDs). For total and calculated free testosterone, the expected inverse association with SHBG levels were observed only for “all-cause” and cancer mortality and not for CVD deaths [18]. Another cohort study showed, in a group with age ranging from 35 to 80 years, that elevated levels in SHBG were positively associated with increased incidental cardiovascular disease risk in men over 65 years [19]. However, it is still unknown whether changes in the circulating plasma levels of SHBG, the local expression of SHBG and androgen-binding proteins in tissues such as the heart, or the secondary effects of SHBG level fluctuations in free testosterone are responsible for these effects. In this review, we are going to discuss the mechanisms currently proposed for SHBG cardioprotective effects and how the use of circulating SHBG levels can be useful as an early metabolic and cardiovascular biomarker.
2. SHBG Is not Only a Passive Carrier for Sex-Steroids
In men, approximately 70% of circulating plasma testosterone binds with high affinity to circulating SHBG, 20–30% to albumin, and the remaining 1-2% circulates in free form [20]. In women, the majority of plasma estradiol and testosterone is bound to SHBG and other proteins and is not bioavailable; only about 2% of these sex hormones are free to bind to receptors and have an impact on the body [21]. Circulating SHBG modulates the level of free sex-steroid hormones that can enter diverse target cells [22]. The endocrinological concept is known as the “free hormone hypothesis” states that the “bioavailable” steroid hormone, i.e., the one that has an effect when bound to its receptor, is the unbound or “free” fraction of steroid hormones [23]. However, recent evidence indicates that circulating SHBG not only is a passive carrier of male sex hormones but also actively regulates testosterone uptake and androgen signaling [24]. Because circulating SHBG binds to sex hormones, the relative plasma levels of this protein can modulate the concentrations of sex-related hormones accessible for use by the body, which has an impact on the processes regulated by the sex hormones [25]. SHBG can also release hormones in specific tissues and cells directly, which can influence both production and effects of sex hormones as well as the expression and function of circulating SHBG. Also, sex hormones bound to circulating SHBG can change the affinity of SHBG to its peripheral receptors. Moreover, intracellular expression of SHBG in testicular proximal tubule cells increases the uptake of dihydrotestosterone and prolongs the expression of androgen-responsive genes [26].
2.1. Circulating SHBG Internalization
2.2. SHBG as an External Ligand
3. Signal Transduction Pathways Involved in SHBG Expression
SHBG is a glycoprotein synthesized and secreted by the liver [46–48] that transports sex-steroids (androgens and estrogens) from steroidogenic organs to their target tissues [6, 20, 24, 49, 50].
4. Effects of SHBG and Testosterone on Cardiac Function: Mechanistic Evidence from Animal and Human Research
Most of the research linking SHBG and androgens has been focused on their circulating levels. If altered levels of circulating SHBG are causally related to high cardiovascular risk, raises the question, what is the potential mechanism?
In humans, plasma SHBG levels are influenced by nutritional state, metabolism, and hormonal factors [9, 58, 96, 97].
*Physiological effects of testosterone in cardiac cells include handling of energy substrates and increased gene expression of key enzymes involved in glucose uptake and glycolysis; and regulation of critical transcription factors related to stimuli that affect cardiomyocyte function
5. Human Diseases and Medications Related to Circulating SHBG
Various human diseases have been associated with altered circulating levels of SHBG, many of which also are linked with high CVD risk (Table 1).
6. Conclusion and Future Research
Given the important roles of androgens in normal men's physiology, abnormal levels must be considered one of the main causes implicated in several disorders and pathological conditions [108, 144–146]. According to a 2017 update demography report from the American Heart Association, almost one in three adult men have some type of cardiovascular disease [147]. In the context of human disease relevance, the international expert consensus panel that convened in 2015 concluded that there is a need for a major research initiative to explore the possible cardioprotective benefits of testosterone therapy, implying that there is sufficient evidence regarding the safety of testosterone therapy in hypogonadal men and that the direction of future research should be set toward defining suitable therapeutic options for cardiovascular disease [148, 149]. Research in the field of androgen signaling will provide a considerable understanding of the physiological and pathological roles of SHBG and sex-steroid hormones. Thus, an appropriate description of testosterone signaling considering circulating and cardiac SHBG expression might help explain both physiological and adverse cardiac metabolic roles of androgens (particularly androgen deficiency). Research directed to elucidate whether plasmatic and cardiac SHBG expression is associated with physiological testosterone levels could represent novel research approaches to study insulin resistance, obesity, diabetes, and heart failure.
