International Journal of Molecular Sciences Review Sex Hormone-Binding Globulin (SHBG) as an Early Biomarker and Therapeutic Target in Polycystic Ovary Syndrome Xianqin Qu 1,* and Richard Donnelly 2 1 School of Life Sciences, University of Technology Sydney, Ultimo, NSW 2007, Australia 2 School of Medicine, University of Nottingham, Derby DE22 3DT, UK; [email protected] * Correspondence: [email protected]; Tel.: +61-2-95147852 Received: 1 October 2020; Accepted: 28 October 2020; Published: 1 November 2020 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. Keywords: adolescents; hepatic lipogenesis; human sex hormone-binding globulin; insulin resistance; non-alcoholic fatty liver disease; polycystic ovary syndrome 1. Introduction Polycystic ovary syndrome (PCOS) is a complex, common reproductive and endocrine disorder affecting up to 10% of reproductive-aged women [1]. Common symptoms of PCOS include irregular menstrual cycles (oligo-ovulation), hyperandrogenism, hirsutism with acne vulgaris and polycystic ovaries [2]. In addition, women with PCOS are often affected by metabolic abnormalities, including obesity, insulin resistance, dyslipidemia, systemic inflammation, non-alcoholic fatty liver disease (NAFLD), and hypertension, as well as an increased risk for type 2 diabetes and cardiovascular disease [3]. The complex and heterogeneous characters of PCOS give challenges in making the diagnosis. Various diagnostic criteria for PCOS and its associated phenotypes have been published. Utilizing the most widely accepted criteria [4–8], PCOS can be described in terms of four different phenotypes (Figure1). The phenotype which includes hyperandrogenism, menstrual irregularities /anovulation and polycystic ovaries (HA + M + PCO) is considered to be the most severe form of PCOS which significantly increases the risk for infertility and adverse pregnancy outcomes [9]. While the aetiology of PCOS remains unclear, it is likely to be multifactorial. No single cause has been identified; however, multiple lines of evidence suggest a complex interplay between genetic and environmental factors [10,11]. Currently, there is no single treatment for PCOS and in clinical practice the therapeutic strategy is usually focused on individualised treatment to manage clinical symptoms and reduce metabolic and cardiovascular risk [12]. Int. J. Mol. Sci. 2020, 21, 8191; doi:10.3390/ijms21218191 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 8191 2 of 17 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 17 Figure 1. DiagnosticDiagnostic criteria criteria and and 4 4main main phenotypes phenotypes o off polycystic polycystic ovary ovary syndrome syndrome (PCOS) (PCOS).. **Hyperandrogenism:Hyperandrogenism: either either testosterone testosterone above above threshold threshold and/or and/or the the presences presences of hirsutism or acne or androgenicandrogenic alopecia.alopecia. *Oligo-anovulation:*Oligo-anovulation: eight eight or lessor less ovulations ovulations per year. per *Polycysticyear. *Polycystic ovaries: ovaries: ovarian ovarianvolume volume> 10 mL > and 10 /morL antral and/or follicles antral numberfollicles number as defined as abovedefined and above less thanand less 9 mm than in size9 mm at leastin size in atone least ovary. in one ovary. WWomenomen with PCOS may may present with a number of of reproductive, reproductive, metabolic, metabolic, psychological and anthropometric complications complications [13 [13,14].,14] For. For example, example, ovarian ovarian dysfunction dysfunction leads to leads anovulatory to anovulatory infertility. infertility.Furthermore, Furthermore, for those women for those who women do become who do pregnant become there pregnant is an increasedthere is an risk increased of miscarriage, risk of miscarriage,foetal complications foetal complications and gestational and diabetes gestational [9,15 diabetes–17]. [9,15–17]. Epidemiological studiesstudies indicate indicate that that the the majority majority of PCOS of PCOS begins begins during during pubertal pubertal growth growth [18,19]. [18To prevent,19]. To prevent PCOS associated PCOS associated comorbidities comorbidities and complications, and complications, it is important it is important to develop to an develop approach an approachthat targets that the targets mechanisms the mechanisms behind PCOS behind at its PCOS earliest at its stages, earliest e.g., stages, in adolescents. e.g., in adolescents. 2. PCOS Diagnosis 2. PCOS Diagnosis 2.1. A Case Report 2.1. A Case Report A 19-year-old girl presents with a history of irregular menses for 4 years. She had undergone pubertyA 19 that-year was-old normal girl presents in both timing with a and history development, of irregular with menses menarche for at4 years. 12 years She of age.had undergoneAt 16 years pubertyof age, she that started was normal irregular in menses both timing with the and cycle development, length varying with between menarche 20 andat 12 60 years days of and age. bleeding At 16 yearsfor about of age, 6 days. she started She reports irregular feeling menses depressed with the about cycle facial length acne. varying Her between weight is20 80 and kg 60 and days height and bleeding1.75 m; body-mass for about index6 days. is She 26.2. reports Physical feeling examination depressed confirms about no facial hirsutism acne. butHer she weight does is have 80 kg severe and heightfacial acne. 1.75 m; body-mass index is 26.2. Physical examination confirms no hirsutism but she does have Investigationssevere facial acne. show that her follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levelsInvestigations are in the normal show ranges that withher follicle low levels-stimulating of estradiol hormone (OEST2) (FSH) and progesterone. and luteinizingTotal hormone testosterone (LH) levelsis 1.1 are nmol in/L the (NR normal 0.6–2.5), ranges dehydroepiandrosterone with low levels of estradiol sulfate (DHEAS)(OEST2) and 5.1 umolprogesterone./L (NR 3.3–12), Total testosteroneand androstenedione is 1.1 nmol/L 7.7 nmol (NR/L 0.6 (NR–2.5), 4.9–14). dehydroepiandro The calculatedsterone free testosterone sulfate (DHEAS) 33.6 pmol 5.1/L (NRumol/L 3.5–46.0) (NR 3.3level–12), is in and the androstenedione normal range but the7.7 serumnmol/L SHBG (NR 4.9 concentration–14). The calculated is only 8 nmol free/ Ltestosterone (NR 20-118). 33.6 Her pmol/L fasting (NRplasma 3.5– glucose46.0) level is 4.9 is mmolin the /normalL, HbA1c range 5.1%, but and the fasting serum insulin SHBG levelconcentration is raised atis 35only mU 8 /nmol/LL(NR < (NR10). 20The-118). lipid Her profile fasting is normalplasma butglucose liver is function 4.9 mmol/L, tests HbA1c are raised: 5.1%, and serum fasting ALT insulin 58 U/L level (NR is< raised30) and at 35abdominal mU/L (NR ultrasound < 10). The shows lipid profile a pattern is normal of diffuse but fatty liver infiltration function tests of the are liver. raised: serum ALT 58 U/L (NR < 30) and abdominal ultrasound shows a pattern of diffuse fatty infiltration of the liver. Int. J. Mol. Sci. 2020, 21, 8191 3 of 17 In addition, the ovarian morphology was unremarkable on ultrasound but an accurate antral follicle count could not be defined (a transvaginal scan was declined by the patient). The diagnosis of PCOS in this woman is supported by the history of irregular menses with a raised BMI and evidence of acne vulgaris. Facial acne is often a complication of androgen excess but her androgen levels were within the normal range. However, her SHBG level was very low, thereby increasing androgen activity which may adversely affect her skin. Investigations also revealed this young woman had evidence of NAFLD and insulin resistance (as shown indirectly by the compensatory hyperinsulinaemia). The history of irregular menstruation would indicate ovarian dysfunction but in this young woman there was neither biochemical hyperandrogenism nor polycystic ovary morphology (PCOM) on ultrasound at this stage. A recent clinical study recommended more simplified criteria for making a diagnosis of PCOS, based on testosterone as a single marker of hyperandrogenaemia alongside the key symptoms of oligomenorrhoea and hyperandrogenism as defined by either testosterone levels above a threshold and/or the presences of hirsutism [20]. Thus, a reasonable question raised by this case history is whether she should have a PCOS diagnosis? If yes, how do we prevent progression from early stages to the more classic and severe phenotype (HA + M + PCO)? 2.2. Clinical Features and Biochemical Assessments of PCOS Adolescents Although PCOS often impacts fertility, the most common manifestations in teenagers include