Elsevier

Clinica Chimica Acta

Volume 499, December 2019, Pages 142-148
Clinica Chimica Acta

Review
Sex hormone-binding globulin and polycystic ovary syndrome

https://doi.org/10.1016/j.cca.2019.09.010Get rights and content

Highlights

  • SHBG, as a transporter of sex hormones, plays an important role in the development and long-term prognosis of PCOS.

  • HNF-4α plays a key role of in hepatic SHBG synthesis, many factors regulate the circulating SHBG levels by regulating HNF-4α expression.

  • This may provide a new direction for the mechanism and clinical treatment of PCOS.

Abstract

Polycystic ovary syndrome (PCOS), one of the most common endocrine diseases that causes infertility in reproductive women, is characterized by hyperandrogenemia, chronic anovulation, and polycystic ovary morphology (PCOM), and most women with PCOS have metabolic abnormalities. A reduction in plasma sex hormone-binding globulin (SHBG), a transport carrier that binds estrogen and androgens and regulates their biological activities, is often used as an indicator of hyperandrogenism in women with PCOS. Low serum SHBG levels are considered a biomarker of abnormal metabolism and are related to insulin resistance (IR), compensatory hyperinsulinemia and abnormalities in glucose and lipid metabolism in PCOS patients. SHBG is also associated with the long-term prognosis of PCOS. SHBG gene polymorphism is correlated with the risk of PCOS. As SHBG plays a vital role in the occurrence and development of PCOS, knowledge regarding its role in PCOS is helpful for further understanding the molecular mechanism of SHBG in PCOS development and providing new ideas for the treatment of female infertility. Hepatocyte nuclear factor-4α (HNF-4α) is a vital transcription factor in the SHBG synthesis process. HNF-4α binds to the cis-type element DR1 in the SHBG promoter to initiate transcription and regulates hepatic SHBG levels by modulating glucose and lipid metabolism and inflammatory factors. However, it remains unclear whether HNF-4α is indirectly involved in the pathogenesis of PCOS via regulation of hepatic SHBG synthesis. Therefore, this review discusses the interaction between SHBG and the various complications of PCOS as well as the regulatory effect of HNF-4α on SHBG expression.

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder that causes infertility in women of childbearing age. PCOS is mainly caused by excess androgens, and it affects 6% to 10% of women worldwide [1]. Furthermore, PCOS is a powerful risk factor for type 2 diabetes (T2D), cardiovascular disease, gestational diabetes, pregnancy-induced hypertension, and endometrial cancer. The clinical manifestations of PCOS are highly heterogeneous, the etiology is still unknown, and the pathological mechanism is very complex and is generally believed to be associated with hypothalamic-pituitary-ovarian axis dysfunction, adrenal dysfunction, heredity, metabolism and other factors. The most widely used diagnostic criteria are those proposed by members of the European Society of Human Reproduction and Embryology and the American Society of Reproductive Medicine in 2003, known as the Rotterdam standard [2]. These criteria propose that PCOS can be diagnosed by meeting two of the following three conditions and excluding other diseases caused by excess androgens: rare ovulation or long-term anovulation, clinical hyperandrogenic signs or biochemical hyperandrogenism, and polycystic ovary morphology (PCOM).

Hyperandrogenism is a key characteristic of PCOS. Clinically, assessment of an excess of female biochemical androgen generally includes detection of total testosterone (TT), free testosterone (FT), and sex hormone-binding globulin (SHBG) or calculation of the free androgen index [3]. As a transporter of sex hormones, SHBG is produced by the liver and binds to circulating sex steroids with high affinity, regulating the concentration of bioactive sex hormones in the blood and affecting their bioavailability [4]. As SHBG exhibits high affinity for testosterone and a low affinity for estradiol, it is an effective auxiliary indicator for the determination of androgen levels [5]. The binding of testosterone by SHBG does not result in biological effects, and only approximately 1–2% of unbound free testosterone has biological activity. Therefore, SHBG can be used to judge the severity of hyperandrogenism and evaluate the therapeutic efficacy of treatment. Previous studies have found that insulin affects SHBG, with hyperinsulinism inhibiting its synthesis and secretion [6]. Compared with levels in healthy individuals, serum SHBG levels are significantly decreased in patients with hyperinsulinemia [7], and low serum SHBG levels may be a risk factor for abnormal glucose metabolism. In general, both hormone levels and serum SHBG levels should be considered in PCOS patients, as they play important roles in the development and prognosis of PCOS in clinical practice.

Hepatocyte nuclear factor-4α (HNF-4α), an orphan receptor, is a member of the nuclear receptor superfamily that is mainly expressed in the liver, intestines, pancreas and kidneys [8]. HNF-4α has an important function in SHBG expression and synthesis, and it is a major transcription factor regulating SHBG gene expression in the liver [9]. Overexpression of SHBG significantly increases HNF-4α mRNA and protein levels and reduces those of PPAR-γ [10], and the positive correlation between SHBG mRNA and HNF-4α mRNA levels has been confirmed in human liver biopsies [10]. Although activation of HNF-4α does not require exogenous ligands, long-chain fatty acids (including palmitate) have been identified as endogenous ligands that may affect the transcriptional activity of HNF-4α [11]. Activated HNF-4α regulates lipid metabolism in the liver, and its target genes are apolipoproteins, including apoA-I, apoB, and apoC-III [12]. Therefore, expression of HNF-4α is related to lipid metabolism disorders, with greater severity with weaker HNF-4α expression. Lipid accumulation reduces hepatic SHBG expression [13], and HNF-4α not only regulates lipid metabolism but also maintains glucose homeostasis by regulating insulin secretion and glycosylation. Nonetheless, it remains unknown whether HNF-4α is involved in PCOS development and long-term prognosis by regulating circulating SHBG levels. Understanding the effects of HNF-4α on SHBG regulation and PCOS development may provide a new perspective regarding the pathogenesis of PCOS. Overall, more research and verification on this topic is needed.

Section snippets

Structure of SHBG and regulation of the SHBG promoter by HNF-4α

The SHBG gene, which contains eight exons and seven introns, is located on chromosome 17p12—p13 [14,15]. Exons 2–8 encode two contiguous laminin G–like (LG) domains [14]. The steroid-binding sites of SHBG are located in the amino-terminal LG domain encoded by exons 2–5 [16]. The SHBG protein is a homologous dimer composed of two identical noncovalently bound subunits [15]. As each SHBG subunit has a steroid-binding site, mature SHBG homodimers have two distinct steroid-binding sites [17].

HNF-4α

The association between low serum SHBG levels and obesity in women with PCOS

Obesity is considered to be one of the most important factors leading to the development of PCOS. Indeed, it is reported that 35–80% of women with PCOS are overweight or obese [25]. The metabolic phenotype of PCOS is exacerbated by obesity, and the incidence of PCOS is higher in overweight and obese patients [6]. With the improvement in living standards, obesity is not only common in adults but has also greatly increased in teenagers and children. In addition to effects of reproductive

The regulatory effect of thyroid hormone on SHBG

In utero, fetuses have a low level of SHBG, though the level starts to rise after birth [57]. There is evidence that the increase in plasma SHBG after birth is caused by the production and maturation of thyroid hormone [58]. Moreover, patients with hyperthyroidism usually have elevated plasma SHBG levels [59]. In vitro studies have shown that thyroid hormone therapy increases the production of hepatic SHBG, as well as levels of SHBG mRNA [60]. However, the SHBG promoter lacks response elements

Inflammatory cytokines associated with HNF-4α-mediated regulation of SHBG

Chronic low-grade inflammation is common in PCOS patients, and it is associated with excess androgens, IR, obesity and atherosclerosis [62]. Obesity-induced chronic low-grade inflammation is an important factor leading to insulin resistance. Common markers include c-reactive protein (CRP), interleukin (IL), tumor necrosis factor-α (TNF-α) and adipokines. Circulating levels of CRP, TNF-α, IL-1 and IL-6 are elevated in PCOS patients [63], and low serum SHBG levels are observed in chronic

The correlation between SHBG gene polymorphism and PCOS

The correlation between SHBG gene polymorphism and serum SHBG levels is attracting increasing attention and research [14,66]. SHBG polymorphisms have been regarded as important predictors of hyperandrogenism in women with PCOS [66]. The motif (TAAAA)n is present in the upstream region of the SHBG promoter, and it has been shown to influence transcriptional activity in vitro [67]. In addition, (TAAAA)n polymorphism affects SHBG mRNA and further affects SHBG levels [68]. Longer repeat sequences

Conclusion and prospects

PCOS is one of the most common diseases affecting infertility in women of childbearing age, and it remains a difficult condition to manage due to a lack of knowledge regarding the pathophysiological mechanisms. Obesity, IR, and abnormal glucose and lipid metabolism show a significant correlation with PCOS. A low serum SHBG level in PCOS patients is not only an important influencing factor for hyperandrogenemia but is also an important predictor of insulin resistance, as well as a risk factor

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgments

This study was supported by grants from the Horizontal Cooperation project with Yueyang Maternal & Child Health-Care Hospital (2018KHX41), the College Students' Research Learning and Innovative Experiment Plan in University of South China (NO. 2017XJYZ049, 2018XJXZ163), the Key Lab for Clinical Anatomy & Reproductive Medicine of Hengyang City (2017KJ182), and the Chuanshan Talents Project in University of South China.

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