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Cited by 212Ovarian function and disordersHormonal and reproductive studiesGenetic and Kidney Cyst Diseases

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Sex Hormone-Binding Globulin (SHBG) as an Early Biomarker and Therapeutic Target in Polycystic Ovary Syndrome

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Qu, Xianqin, Donnelly, Richard·2020·International Journal of Molecular Sciences
DOI 10.3390/ijms21218191PMC PMC7663738
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Abstract

Human sex hormone-binding globulin (SHBG) is a glycoprotein produced by the liver that binds sex steroids with high affinity and specificity. Clinical observations and reports in the literature have suggested a negative correlation between circulating SHBG levels and markers of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. Decreased SHBG levels increase the bioavailability of androgens, which in turn leads to progression of ovarian pathology, anovulation and the phenotypic characteristics of polycystic ovarian syndrome (PCOS). This review will use a case report to illustrate the inter-relationships between SHBG, NAFLD and PCOS. In particular, we will review the evidence that low hepatic SHBG production may be a key step in the pathogenesis of PCOS. Furthermore, there is emerging evidence that serum SHBG levels may be useful as a diagnostic biomarker and therapeutic target for managing women with PCOS.

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Figure 1 Diagnostic criteria and 4 main phenotypes of polycystic ovary syndrome (PCOS). *Hyperandrogenism: either testosterone above threshold and/or the presences of hirsutism or acne or androgenic alopecia. *Oligo-anovulation: eight or less ovulations per year. *Polycystic ovaries: ovarian volume > 10 mL and/or antral follicles number as defined above and less than 9 mm in size at least in one ovary.
Figure 1 Diagnostic criteria and 4 main phenotypes of polycystic ovary syndrome (PCOS). *Hyperandrogenism: either testosterone above threshold and/or the presences of hirsutism or acne or androgenic alopecia. *Oligo-anovulation: eight or less ovulations per year. *Polycystic ovaries: ovarian volume > 10 mL and/or antral follicles number as defined above and less than 9 mm in size at least in one ovary.CC BY · PubMed Central
Figure 2 The molecular mechanism by which insulin resistance mediates various factors/pathways that reduce SHBG production, in part by down-regulating HNF-4α in the liver. (1) Hepatic insulin resistance with dietary factors (fructose and sucrose) increases monosaccharide delivery to the liver to cause reduction of hepatic HNF-4α levels and SHBG production through stimulating sterol regulatory element binding protein 1c (SREBP-1c), which promotes hepatic de no lipogenesis (DNL) by enhancing the transcription of several lipogenic enzymes, notably adenosine triphosphate citrate lyase (ACL), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS), and stearoyl-CoA desaturase (SCD1). (2) Obesity and insulin resistance increase adipose lipolysis to deliver NEFAs and lipid intermediates to promote gluconeogenesis and lipogenesis, subsequently inhibiting HNF-4α and reducing SHB. (3) Obesity with adipose insulin resistance increases pre-inflammatory cytokines: TNF-α downregulates HNF-4α expression through NF-κB activation; IL-1β decreases HNF-4α expression through the MEK-1/2 and JNK-MAPK pathways; adiponectin increases HNF-4α levels through AMPK activation. Reduction of adiponectin increases hepatic lipogenesis and thereby leading to downregulation of HNF-4α. (4) HNF-4α increases SHBG transcriptional activity by binding to the cis-elements DR1 and DR3 in the SHBG promoter. (5) Enhanced DNL inhibits HNF-4α and stimulates PPAR-γ expression which competes with HNF-4α for binding to DR3 and inhibits SHBG transcriptional activity, attenuating SHBG expression and reduced SHBG secretion. Words or arrows in red color are used to emphasize the key factors involved in insulin resistance mediated SHBG production.
Figure 2 The molecular mechanism by which insulin resistance mediates various factors/pathways that reduce SHBG production, in part by down-regulating HNF-4α in the liver. (1) Hepatic insulin resistance with dietary factors (fructose and sucrose) increases monosaccharide delivery to the liver to cause reduction of hepatic HNF-4α levels and SHBG production through stimulating sterol regulatory element binding protein 1c (SREBP-1c), which promotes hepatic de no lipogenesis (DNL) by enhancing the transcription of several lipogenic enzymes, notably adenosine triphosphate citrate lyase (ACL), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS), and stearoyl-CoA desaturase (SCD1). (2) Obesity and insulin resistance increase adipose lipolysis to deliver NEFAs and lipid intermediates to promote gluconeogenesis and lipogenesis, subsequently inhibiting HNF-4α and reducing SHB. (3) Obesity with adipose insulin resistance increases pre-inflammatory cytokines: TNF-α downregulates HNF-4α expression through NF-κB activation; IL-1β decreases HNF-4α expression through the MEK-1/2 and JNK-MAPK pathways; adiponectin increases HNF-4α levels through AMPK activation. Reduction of adiponectin increases hepatic lipogenesis and thereby leading to downregulation of HNF-4α. (4) HNF-4α increases SHBG transcriptional activity by binding to the cis-elements DR1 and DR3 in the SHBG promoter. (5) Enhanced DNL inhibits HNF-4α and stimulates PPAR-γ expression which competes with HNF-4α for binding to DR3 and inhibits SHBG transcriptional activity, attenuating SHBG expression and reduced SHBG secretion. Words or arrows in red color are used to emphasize the key factors involved in insulin resistance mediated SHBG production.CC BY · PubMed Central
Figure 3 Schematic representation of the putative mechanisms linking low SHBG with the development NAFLD and PCOS. Increased hepatic de no lipogenesis inhibits SHBG synthesis through downregulating HNF-4α, leading to increasing androgen bioavailability and disrupting negative feedback relationship of hypothalamic–pituitary–ovarian axis, subsequently resulting in higher levels of LH and lower levels of FSH in most women with PCOS. Higher LH levels seem to cause hyperandrogenemia by exuberating androgens secretion from follicular theca cells, whereas lower FSH levels lead to anovulation. System insulin resistance associated with inflammatory cytokines directly induces granulosa cells apoptosis, leading to arrested follicular maturation, contribute to anovulation and multiple cystic follicles (CF) formation in PCOS.
Figure 3 Schematic representation of the putative mechanisms linking low SHBG with the development NAFLD and PCOS. Increased hepatic de no lipogenesis inhibits SHBG synthesis through downregulating HNF-4α, leading to increasing androgen bioavailability and disrupting negative feedback relationship of hypothalamic–pituitary–ovarian axis, subsequently resulting in higher levels of LH and lower levels of FSH in most women with PCOS. Higher LH levels seem to cause hyperandrogenemia by exuberating androgens secretion from follicular theca cells, whereas lower FSH levels lead to anovulation. System insulin resistance associated with inflammatory cytokines directly induces granulosa cells apoptosis, leading to arrested follicular maturation, contribute to anovulation and multiple cystic follicles (CF) formation in PCOS.CC BY · PubMed Central

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  1. Johnson, T., Kaplan, L., Ouyang, P., Rizza, R., and Health, N.I.O. (2012). Evidence-Based Methodology Workshop on Polycystic Ovary Syndrome.

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Metadata

Authors
Qu, X., & Donnelly, R.
Affiliations
  • University of Technology Sydney (AU)
  • University of Nottingham (GB)
Corresponding author
Qu, Xianqin
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2020-11-01
Volume
21
Issue
21
Pages
8191
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms21218191
PMC
PMC7663738
OpenAlex
W3096809272
Cited by
210
References
114
Citations by year
2026: 40 · 2025: 46 · 2024: 47 · 2023: 35 · 2022: 29 · 2021: 13
FWCI
16.98
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • UTS ePRESS (University of Technology Sydney) (submittedVersion)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
Keywords
sex hormone-binding globulin, polycystic ovary syndrome, non-alcoholic fatty liver disease, insulin resistance, diagnostic biomarkers, therapeutic target, PCOS pathogenesis
MeSH terms
Female, Humans, Insulin Resistance, Polycystic Ovary Syndrome, Sensitivity and Specificity, Sex Hormone-Binding Globulin, Biomarkers, Young Adult, Molecular Targeted Therapy, Non-alcoholic Fatty Liver Disease

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