ReviewSex hormone-binding globulin and polycystic ovary syndrome
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.
References (80)
Diagnosis of hyperandrogenism: biochemical criteria
Best Pract. Res. Clin. Endocrinol. Metab.
(2006)- et al.
Hepatocyte nuclear factor-4 controls transcription from a TATA-less human sex hormone-binding globulin gene promoter
J. Biol. Chem.
(1998) - et al.
Crystal structure of the HNF4 alpha ligand binding domain in complex with endogenous fatty acid ligand
J. Biol. Chem.
(2002) - et al.
Genetic variants of sex hormone-binding globulin and their biological consequences
Mol. Cell. Endocrinol.
(2010) The plasma sex steroid binding protein (SBP or SHBG). A critical review of recent developments on the structure, molecular biology and function
J. Steroid Biochem. Mol. Biol.
(1991)- et al.
Resolution of the human sex hormone-binding globulin dimer interface and evidence for two steroid-binding sites per homodimer
J. Biol. Chem.
(2001) - et al.
Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome
Mol. Cell. Endocrinol.
(2010) - et al.
Novel insights in SHBG regulation and clinical implications
Trends Endocrinol. Metab.
(2015) - et al.
Associations of adiponectin with sex hormone-binding globulin levels in aging male and female populations
Clin. Chim. Acta
(2007) - et al.
Serum asymmetric dimethylarginine, apelin, and tumor necrosis factor-alpha levels in non-obese women with polycystic ovary syndrome
Steroids
(2012)
Human sex hormone-binding globulin promoter activity is influenced by a (TAAAA)n repeat element within an Alu sequence
J. Biol. Chem.
Evaluating reported candidate gene associations with polycystic ovary syndrome
Fertil. Steril.
Hepatocyte nuclear factor-4alpha P2 promoter variants are associated with the risk of metabolic syndrome and testosterone deficiency in aging Taiwanese men
J. Sex. Med.
The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis
Hum. Reprod.
Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS)
Hum. Reprod.
Evolving utility of sex hormone-binding globulin measurements in clinical medicine
Curr. Opin .Endocrinol .Diabetes .Obes
Testosterone effects on the breast: implications for testosterone therapy for women
Endocr. Rev.
The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis
Obes. Rev.
Sex hormone binding globulin as a valuable biochemical marker in predicting gestational diabetes mellitus
BMC Womens Health
Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily
Genes Dev.
SHBG-C57BL/ksJ-db/db: a new mouse model to study SHBG expression and regulation during obesity development
Endocrinology
Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis
Mol. Cell. Biol.
Adiponectin upregulates SHBG production: molecular mechanisms and potential implications
Endocrinology
Diverse roles for sex hormone-binding globulin in reproduction
Biol. Reprod.
Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4alpha
J. Mol. Endocrinol.
Potential role of tumor necrosis factor-alpha in downregulating sex hormone-binding globulin
Diabetes
Molecular mechanism of TNFalpha-induced Down-regulation of SHBG expression
Mol. Endocrinol.
IL1beta down-regulation of sex hormone-binding globulin production by decreasing HNF-4alpha via MEK-1/2 and JNK MAPK pathways
Mol. Endocrinol.
Oleic acid increases hepatic sex hormone binding globulin production in men
Mol. Nutr. Food Res.
Peroxisome-proliferator receptor gamma represses hepatic sex hormone-binding globulin expression
Endocrinology
Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial
J. Clin. Endocrinol. Metab.
Body mass index and ovarian function are associated with endocrine and metabolic abnormalities in women with hyperandrogenic syndrome
Eur. J. Endocrinol.
Abnormal sex steroid secretion and binding in massively obese women
Clin. Endocrinol.
Sex differences in effects of obesity on reproductive hormones and glucose metabolism in early puberty
J. Clin. Endocrinol. Metab.
Circulating steroid hormone concentrations in postmenopausal women in relation to body size and composition
Breast Cancer Res. Treat.
Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic-hyperinsulinaemic clamp studies
Hum. Reprod.
Insulin resistance and adverse metabolic profile in overweight/obese and normal weight of young women with polycystic ovary syndrome
Caspian J Intern Med
Genetic variants associated with hyperandrogenemia in PCOS pathophysiology
Genet. Res. Int.
Lifestyle changes in women with polycystic ovary syndrome
Cochrane Database Syst. Rev.
The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest
Hum. Reprod. Update
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The first two authors contributed equally to this paper.