Trends in Endocrinology & Metabolism
ReviewNovel insights in SHBG regulation and clinical implications
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.
References (80)
Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome
Mol. Cell. Endocrinol.
(2010)Sex-hormone binding globulin and protein–energy malnutrition indexes as indicators of nutritional status in women with anorexia nervosa
Am. J. Clin. Nutr.
(1993)Serum sex hormone-binding globulin levels are independently associated with nonalcoholic fatty liver disease in people with type 2 diabetes
Diabetes Res. Clin. Pract.
(2011)Polycystic ovary syndrome
Lancet
(2007)Sex hormone-binding globulin and type 2 diabetes mellitus
Trends Endocrinol. Metab.
(2012)Associations of adiponectin with sex hormone-binding globulin levels in aging male and female populations
Clin. Chim. Acta
(2007)Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity
Biochem. Biophys. Res. Commun.
(1999)IL-32γ overexpression accelerates streptozotocin (STZ)-induced type 1 diabetes
Cytokine
(2014)Effects of acute hyperinsulinemia on testosterone serum concentrations in adult obese and normal-weight men
Metabolism
(1997)The regulation of rotenone-induced inflammatory factor production by ATP-sensitive potassium channel expressed in BV-2 cells
Neurosci. Lett.
(2006)
Male hypogonadism in systemic disease
Endocrinol. Metab. Clin. North Am.
Olive oil and health: summary of the II international conference on olive oil and health consensus report, Jaén and Córdoba (Spain) 2008
Nutr. Metab. Cardiovasc. Dis.
Structure, function, and regulation of androgen-binding protein/sex hormone-binding globulin
Vitam. Horm.
Hepatocyte nuclear factor-4 controls transcription from a TATA-less human sex hormone-binding globulin gene promoter
J. Biol. Chem.
Low serum testosterone and sex-hormone-binding-globulin in massively obese men
J. Clin. Endocrinol. Metab.
Sex hormone-binding globulin and risk of type 2 diabetes
N. Engl. J. Med.
Relationships of circulating sex hormone-binding globulin with metabolic traits in humans
Diabetes
Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men
Diabetes Care
Sex hormone-binding globulin and insulin-like growth factor-binding protein-1 as indicators of metabolic syndrome, cardiovascular risk, and mortality in elderly men
J. Clin. Endocrinol. Metab.
Sex hormone-binding globulin and risk of type 2 diabetes in women and men
N. Engl. J. Med.
Decreased sex hormone-binding globulin predicts noninsulin-dependent diabetes mellitus in women but not in men
J. Clin. Endocrinol. Metab.
Low sex-hormone-binding globulin concentration as independent risk factor for development of NIDDM. 12-year follow-up of population study of women in Gothenburg, Sweden
Diabetes
Sex-hormone-binding globulin and the free androgen index are related to cardiovascular risk factors in multiethnic premenopausal and perimenopausal women enrolled in the Study of Women Across the Nation (SWAN)
Circulation
Association of decreased sex hormone binding globulin and cardiovascular risk factors
Arteriosclerosis
Concentrations of sex-hormone binding globulin and corticosteroid binding globulin in serum in relation to cardiovascular risk factors and to 12-year incidence of cardiovascular disease and overall mortality in postmenopausal women
Clin. Chem.
Clinical utility of sex hormone-binding globulin measurement
Horm. Res.
Sex-hormone-binding globulin
Clin. Endocrinol.
Changes in plasma levels of androgens and SHBG in patients with polycystic ovary syndrome (PCOS) treated with oral contraceptives containing desogestrel
Minerva Ginecol.
Plasma level of testosterone–estradiol-binding globulin in women with Itsenko–Cushing disease
Probl. Endokrinol. (Mosk.)
Inter-relations between growth hormone, insulin, insulin-like growth factor-I (IGF-I), IGF-binding protein-1 (IGFBP-1) and sex hormone-binding globulin in acromegaly
Clin. Endocrinol. (Oxf.)
Changes in sex hormone-binding globulin and testosterone during weight loss and weight maintenance in abdominally obese men with the metabolic syndrome
Diabetes Obes. Metab.
Sex hormone-binding globulin predicts the incidence of hyperglycemia in women: interactions with adiponectin levels
Eur. J. Endocrinol.
Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduces the risk of type 2 diabetes
Hum. Mol. Genet.
Association of testosterone and sex hormone-binding globulin with metabolic syndrome and insulin resistance in men
Diabetes Care
Comment on Hedderson et al. Prepregnancy SHBG concentrations and risk for subsequently developing gestational diabetes mellitus
Diabetes Care 2014
Sex hormone binding globulin and insulin resistance
Clin. Endocrinol. (Oxf.)
The role of hepatokines in metabolism
Nat. Rev. Endocrinol.
Sex hormone-binding globulin in the diagnosis of peripheral tissue resistance to thyroid hormone: the value of changes after short term triiodothyronine administration
J. Clin. Endocrinol. Metab.
Effects of thyroid hormone on sex hormone-binding globulin gene expression in human cells
J. Clin. Endocrinol. Metab.
Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4α
J. Mol. Endocrinol.
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