Classic and Novel Sex Hormone Binding Globulin Effects on the Cardiovascular System in Men

Abstract

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 local 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 γ (PPARγ) and AMP-activated protein kinase (AMPK). AMPK/PPAR interaction is critical to regulate 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.

Figure 1

Signaling pathways activated by SHBG. The figure illustrates the action mechanism of SHBG as a hormone carrier and SHBG direct actions. (1) Free circulating androgens and estrogens that correspond to the bioavailable portion of sex hormones can cross the plasma membrane and bind intracellular sex hormone receptors, thus activating the “classic,” genomic sex hormone intracellular pathways. (2) As described in the literature, free circulating sex hormones can also bind to putative membrane receptors activating “fast, nongenomic intracellular signaling pathways.” (3) Another putative membrane receptor, for SHBG, can also activate intracellular signaling pathways, leading to fast, nongenomic effects. (4) The megalin receptor, which induce the internalization of SHBG and a retrograde pathway that affects nuclear and mitochondrial function, can also account for some SHBG-induced intracellular effects.

Figure 2

Hypothetical pathways leading to SHBG expression and their modulation in the heart. A hypothetical intracellular pathway for SHBG expression in the cardiomyocytes. The same membrane receptors modulating SHBG expression in the liver could be expressed in the heart. Metabolic cues modulate the activity of the transcription factor hepatocyte nuclear factor 4-α (HNF4α), which leads to an increase in SHBG gene expression. The following are some of the questions that arise relating to the possible production and secretion of SHBG as an endocrine or paracrine mediator: (1) Can TNFα, IL-1β, and adiponectin modulate SHBG expression in cardiac tissue? (2) Is the heart involved in the release of soluble SHBG in a paracrine or endocrine way? (3) Can soluble SHBG trigger intracellular signaling pathways in the heart?