Review
Novel insights in SHBG regulation and clinical implications

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Highlights

Sex hormone-binding globulin (SHBG) is produced and secreted by the liver into the bloodstream where it binds sex steroids and regulates their bioavailability. Traditionally, body mass index (BMI) was thought to be the major determinant of SHBG concentrations and hyperinsulinemia the main cause for low SHBG levels found in obesity. However, no mechanisms have ever been described. Emerging evidence now shows that liver fat content rather than BMI is a strong determinant of circulating SHBG. In this review we discuss evidence demonstrating that insulin might not regulate SHBG production, describe putative molecular mechanisms by which proinflammatory cytokines downregulate SHBG, and comment on recent findings suggesting dietary SHBG regulation. Finally, clinical implications of all of these findings and future perspectives are discussed.

Section snippets

SHBG: basic concepts

SHBG is expressed in the human liver under the control of hormones and nutritional factors [1]. The human liver secretes SHBG into the blood where it binds androgens and estrogens with high affinity, regulating their bioavailability. BMI has been thought to be a major determinant of circulating SHBG concentrations and a negative correlation between BMI and SHBG plasma levels has been consistently reported [2]. However, in recent years it has been demonstrated that liver fat content rather than

Plasma SHBG level as a biomarker of human disease

SHBG plasma levels are altered in several diseases including obesity [2], anorexia nervosa [14], thyroid hormone disorders [15], polycystic ovary syndrome (PCOS) [16], Cushing's syndrome [17], and acromegaly [18]. In addition, as previously mentioned, epidemiological studies have shown that low plasma SHBG levels are predictive of a higher risk for developing metabolic syndrome [5], T2D 7, 8, 9, and CVD 10, 11, 12.

The potential role of SHBG in the pathogenesis of the above-mentioned diseases

SHBG regulation by cytokines

There is epidemiologic evidence showing a correlation between the plasma levels of several cytokines and plasma SHBG levels in humans. Patients with low-grade chronic inflammatory diseases (i.e., obesity, diabetes, rheumatoid arthritis, or osteoarthritis), in which there is an increase in circulating proinflammatory cytokines, exhibit low plasma SHBG levels 5, 6, 7, 8, 9, 32. Moreover, several epidemiologic studies have reported a positive relationship between adiponectin and SHBG plasma levels

SHBG expression and the role of insulin

The reason why plasma SHBG levels are invariably low in obese males and females of all ages has been the subject of debate during past decades. In the 1980s it was widely accepted that elevated insulin, by an unknown mechanism, produces a decrease in the hepatic production of SHBG [44]. This concept was supported by several reports showing a clear inverse relationship between serum insulin and SHBG levels 45, 46, 47, 48. However, recent in vitro and in vivo evidence has seriously questioned

Dietary SHBG regulation

During the past decade, several studies have shown that numerous dietary components are involved in the regulation of SHBG production in the liver, and some of the underlying molecular mechanisms have been identified (Figure 1).

Clinical implications and future perspectives

One of the most important outcomes of the new insights from SHBG research reported in recent years is that the notion that insulin regulates SHBG serum levels be reconsidered (Box 2). Although numerous studies have shown a univariate inverse relationship between serum insulin and SHBG plasma levels, this may not necessarily imply that insulin downregulates SHBG. Indeed, activation of the TNFα system [assessed by measuring TNFα receptor 1 (TNFα-R1)], but not insulin levels, independently

Concluding remarks

The recent novel insights from basic research and clinical pilot studies discussed here have changed our understanding of the regulation of SHBG and its clinical implications. The crosstalk between inflammation, T2D, sex steroids, and the risk for CVD seems to converge on a reduction in the levels of SHBG. Future research to decipher the underlying molecular mechanisms involved in this relationship and to explore the potential therapeutic action of SHBG is warranted.

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