Current Perspectives on Nonalcoholic Fatty Liver Disease in Women with Polycystic Ovary Syndrome
Received 14 February 2022
Accepted for publication 31 March 2022
Published 24 April 2022 Volume 2022:15 Pages 1281—1291
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Konstantinos Tziomalos
Dongxu Wang,1 Bing He2
1Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China; 2Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China
Correspondence: Bing He, Department of Endocrinology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Shenyang, 110004, People’s Republic of China, Tel/Fax +86-24-96615-23111, Email [email protected]
Abstract: Polycystic ovary syndrome (PCOS) is one of the most common reproductive, endocrine, and metabolic disorders in premenopausal women. Clinically, PCOS is mainly caused by androgen excess and ovarian dysfunction, manifested by anovulatory menstrual cycles, infertility, and hirsutism. In addition, PCOS increases the risk of insulin resistance, obesity, cardiovascular disease, anxiety and depression, dyslipidemia, and endometrial cancer. Nonalcoholic fatty liver disease (NAFLD) is defined as ≥ 5% fat accumulation in the liver in the absence of remaining secondary causes and has become one of the most common chronic liver diseases worldwide. The prevalence of NAFLD is significantly higher and more severe in women with PCOS, and its pathogenesis can be associated with various risk factors such as hyperandrogenemia, insulin resistance, obesity, chronic low-grade inflammation, and genetic factors. Although there is no definitive solution for the management of NAFLD in PCOS, some progress has been made. Lifestyle modification should be the basis of management, and drugs to improve metabolism, such as insulin sensitizers and glucagon-like peptide-1 agonists, may show better efficacy. Bariatric surgery may also be a treatment of NAFLD in obese women with PCOS. This paper reviews three aspects of prevalence, risk factors, and management, in order to better understand the current state of research on NAFLD in PCOS, to explore the pathogenesis of NAFLD in PCOS, and to encourage further research on the application of drugs in this field.
Keywords: polycystic ovary syndrome, nonalcoholic fatty liver disease, hyperandrogenemia, insulin resistance, obesity, metformin, glucagon-like peptide-1
Polycystic ovary syndrome (PCOS) is one of the most common reproductive, endocrine, and metabolic disorders in premenopausal women.1 PCOS is a group of syndromes caused by excessive androgens and ovarian dysfunction.2 Diagnostic criteria for PCOS vary internationally and mainly follow the standards proposed by the National Institutes of Health (NIH) of the United States in 1990,3 the Rotterdam standards proposed by the European Society of Reproductive Medicine and the American Society of Reproductive Medicine in 2003,4 and the Androgen Excess Society (AES) standard proposed by the American Androgen Hypertrophy Society in 2006,5 as shown in Table 1. The Rotterdam standard is currently the most widely used, and the worldwide prevalence of PCOS varies somewhat depending on the diagnostic criteria, ranging from 4% to 21%.6 The clinical manifestations of PCOS are mainly anovulatory menstrual cycles, infertility, and hirsutism.7 In addition, PCOS increases the risk of insulin resistance, obesity, cardiovascular disease, anxiety and depression, dyslipidemia, and endometrial cancer.8–12
Table 1 Diagnostic Criteria for PCOS
Nonalcoholic fatty liver disease (NAFLD) is defined as ≥5% fat accumulation in the liver with the absence of remaining secondary causes, such as viral hepatitis, excessive alcohol consumption, drug-related liver disease, autoimmune liver disease, genetic metabolic liver disease, and other diseases.13 NAFLD includes a wide range of histological changes from simple fat accumulation in the liver to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, and even hepatocellular carcinoma (HCC).14 With a global prevalence of 25.24%,15 NAFLD has become one of the most common chronic liver diseases worldwide and may become a major cause of end-stage liver disease in the coming decades. As a result, NAFLD has gained the attention of physicians, experts, and health policy makers worldwide.16
Recent studies have found a significant increase in the prevalence of NAFLD in PCOS. Therefore, in this review, we will discuss the research progress of NAFLD in PCOS from three aspects: prevalence, risk factors, and management.
Prevalence of NAFLD in PCOS
In 2005, Brown et al17 reported a 24-year-old patient with PCOS and chronically elevated serum transaminase levels who had a liver biopsy confirming severe NASH. Since then, there has been a gradual increase in clinical studies on NAFLD in PCOS, according to the data reported in the studies, we found that the prevalence range for NAFLD in PCOS was 14.5%–77%,18–38 with relevant studies shown in Table 2. There are some differences in the prevalence of NAFLD in PCOS depending on the diagnostic criteria for PCOS. In studies with NIH as the diagnostic criteria, the prevalence ranged from 14.5%–54.5%.18,19 In studies with AES as the diagnostic criteria, the prevalence range for PCOS combined with NAFLD was 23.8%–36.8%.21,22,28 Lastly, in studies with Rotterdam criteria, the prevalence range for PCOS combined with NAFLD was 32.9%–77.0%.20,23–27,29–38 The Rotterdam criteria have a broader definition of PCOS and incorporate more phenotypes, resulting in an increased base of PCOS diagnoses and thus more patients being screened for NAFLD. From a regional perspective, current studies of NAFLD in PCOS have focused on the Americas, Europe, and Asia, with the average prevalence in Asia being lower than that in the Americas and Europe. This regional variation may be related to dietary habits and the levels of economic development between different regions. In addition, a greater prevalence of NASH was found in PCOS compared to controls by biopsies (44.0% vs 20.8%),23 and the prevalence of significant fibrosis in PCOS was 6.9%.38
Table 2 Studies on Prevalence of NAFLD in PCOS
Risk Factors for NAFLD in PCOS
Results from a study of 102 women with pathologically confirmed NAFLD showed that NAFLD was more severe in PCOS, with higher rates of severe ballooning, fibrosis, and advanced fibrosis than those without PCOS; further, the median age of women with advanced liver fibrosis was 5 years earlier in those with PCOS than those without PCOS.39 The main risk factors for NAFLD in PCOS include hyperandrogenemia (HA), insulin resistance (IR), obesity, chronic low grade inflammation, and genetic factors.
Pulses of sustained high-frequency gonadotropin releasing hormone (GnRH) in patients with PCOS cause an increase in the amplitude of LH pulses, resulting in excessive luteinizing hormone (LH) secretion and a relative lack of follicle stimulating hormone (FSH), which causes HA.40 HA is an independent predictor of NAFLD in PCOS,34 and patients with PCOS and HA have more pronounced steatosis than patients with PCOS who do not have HA.41 HA is also an independent risk factor for NAFLD in non-obese patients with PCOS.30 In a clinical study by Petta et al,32 in which liver fibrosis was assessed with the Fibrosis 4 Score (FIB-4), higher FIB-4 was independently associated with higher FAI in nonobese PCOS patients. A low-dose dihydrotestosterone (DHT)-induced model of normal weight PCOS-like female mice with NAFLD showed that DHT enhanced the binding of an androgen receptor (AR) to an androgen response element (ARE) in sterol regulatory element-binding protein (SREBP) cleavage activating protein (SCAP) intron 8, elevating the SCAP-SREBP1 interaction, leading to an increase in nuclear SREBP1, and resulting in increased hepatic adipose de novo synthesis.42 According to the literature, PCOS-like rats with 12 weeks of induced DHT exposure showed that chronic androgen overload leads to insulin resistance and hepatic steatosis by affecting mitochondrial function and causing apoptosis and autophagy imbalance.43 In letrozole-induced PCOS-like rat models and DHT-treated HepG2 models, excess androgens cause steatosis by inhibiting the adenosine monophosphate (AMP)-activated protein kinase alpha pathway.44 Androgens can also lead to impaired branched-chain amino acid metabolism and dysfunctional activity of ELOVL2, SLC22A4, and SLC16A9, contributing to the development of NAFLD.45 In addition, androgens can induce mitochondrial β-oxidation imbalance and de novo lipogenesis through PPARα/β-Srebp1/2-Acc1 and can exacerbate liver inflammatory damage by upregulating the expressions of IL-6, TNF-α, MCP-1, and IL-1β.46 Thus, HA influences the development and progression of NAFLD in PCOS by affecting hepatic lipid metabolism, apoptosis and autophagy imbalance, branched-chain amino acid metabolism, and inflammation.
IR occurs in 50–70% of women with PCOS who have a normal body mass index (BMI), but it is more prevalent in women with PCOS who are overweight or obese.47 While there is an overlap of variants in the genetic regions of IRNS, THADA, and HMGA between PCOS and type 2 diabetes,48 there are intrinsic or acquired defects in the insulin signaling pathway in PCOS.49 In addition, HA and chronic low-grade inflammation in PCOS promote the progression of IR, and therefore, there is a significant presence of IR in patients with PCOS. Among the mechanisms of NAFLD, IR has been well recognized in the pathogenesis of NAFLD, both in the traditional “second strike” theory and the more recent “multiple strike” theory. Several clinical studies have confirmed that IR is a risk factor for NAFLD in PCOS and is associated with liver fibrosis in patients with PCOS.29,31–33 In IR, peripheral tissues are less sensitive and metabolically responsive to circulating insulin, and the inhibitory effect of insulin on lipolysis in peripheral adipose tissue is reduced, resulting in ectopic deposition of large amounts of free fatty acids in the liver.50 Elevated glucose and insulin during IR promote de novo production of intrahepatic fat by activating ChREBP and SREBP1c, respectively.51 IR causes liver damage through increased lipotoxicity, oxidative stress, and activation of the inflammatory cascade;52 it also causes liver fibrosis by activating hepatic stellate cells and promoting excessive production of extracellular matrix through direct and indirect pathways.53 Increased α- smooth muscle actin protein expression was observed in insulin+human chorionic gonadotropin (hCG)-treated rats, both hCG-treated and insulin+hCG-treated rats had increased mRNA expression of transforming growth factor-β and connective tissue growth factor, which were associated with liver fibrosis.46 Therefore, IR is an important risk factor for NAFLD in PCOS.
In a clinical study by Shengir et al,38 the percentage of central obesity in women with PCOS was 96% when waist circumference was used as a criterion. Using BMI as the criterion, the proportion of overweight patients was 11.9%, and the proportion of obese patients was 71.3%.38 This indicates that obesity is prevalent in women with PCOS. PCOS causes weight gain and obesity, which is related to the lipolytic function of androgens on adipocytes. Testosterone contributes to the release of non-esterified fatty acids from visceral adipocytes in the body and impairs adipocyte differentiation and adipokine formation,54 leading to the accumulation of local adipose tissue, especially in the abdomen. Obesity is also associated with lower postprandial thermogenesis, depressed mood and mental health, and lack of exercise in women with PCOS.55 A systematic review and meta-analysis of 7148 patients included in 23 studies showed that premenopausal patients with PCOS had a 2.5-fold increased risk of nonalcoholic fatty liver disease compared to controls, with BMI being a main factor.56 Obesity reduces the level of SFRP5 and its anti-inflammatory effect in the liver;57 it also reduces the level of NRG4 and weakens the regulatory effect of NRG4 on hepatic lipogenesis.58 Lipodystrophy occurs in obesity, and the ability of adipose tissue to store excess energy is diminished, causing hepatocytes to store excess lipids.59 Furthermore, the balance of adipokines is disrupted in obesity, and the secreted adipokines are shifted towards a more adipogenic, inflammatory and fibrogenic direction.60 Through these mechanisms, obesity can exacerbate NAFLD in PCOS.
Chronic Low-Grade Inflammation
Chronic low-grade inflammation in PCOS can be mediated by obesity and HA.61 The hypertrophy of adipocytes in PCOS causes interstitial vascular compression, resulting in inadequate perfusion and hypoxia in adipose tissue, which in turn stimulates the activation of NF-κB and regulates the expression of key genes involved in the inflammatory response.62 This process induces the production and release of many mediators and triggers chronic low-level inflammation in the body, among which IL6 and IL1β can also stimulate the synthesis of CRP in the liver.62 The compensatory process of cellular hypertrophy and proliferation of functionally impaired adipocytes produces a large number of cytokines that induce inflammatory responses, cell damage, and apoptosis.63 A variety of immune cells (eg macrophages, T lymphocytes, etc) also infiltrate during adipocyte hypertrophy, producing cytokines that interact with adipokines and cause an imbalance between pro- and anti-inflammatory cytokines which leads to liver inflammation.64,65 Significant increases in hepatic TNF-α in hepatic expression and mRNA expression of urocortin-1 were observed in the DHT-induced PCOS rat model,66 confirming that PCOS can affect liver function by altering the levels of inflammatory factors and stress-related proteins.
Genetic factors have also been associated with NAFLD in PCOS. Analysis of single nucleotide polymorphisms in cannabinoid receptor 1 (CNR1) in 173 women with PCOS and 125 age-and weight-matched healthy control patients indicated that the G allele of rs806381 was phenotypically associated with NAFLD in PCOS, suggesting a potential role for CNR1 polymorphisms in NAFLD in PCOS.67 Genetic analysis of adipose tissue from patients with NAFLD and PCOS and patients with NAFLD without PCOS showed that reduced LDLR gene expression may be associated with NAFLD in PCOS.68 However, it has also been shown that the rs328 and rs268 polymorphisms of the lipoprotein lipase gene do not affect the occurrence of NAFLD in women with PCOS and in women without PCOS.69 Therefore, we need further in-depth studies on the role of genetic factors in NAFLD with PCOS.
Risk factors can also interact with each other. Dehydroepiandrosterone (DHEA)-induced PCOS-like mice exhibit IR in skeletal muscle, which is associated with androgens inhibiting autophagy, damaging mitochondria, and reducing plasma membrane glucose transporter 4 (GLUT4) expression in mouse skeletal muscle through activation of mTOC1.70 In cultured skeletal muscle cells and skin fibroblasts, androgens have been observed to increase serine phosphorylation of insulin receptors, affecting insulin signaling pathways and triggering IR.71,72 Insulin also acts on the anterior pituitary to enhance the release of GnRH, which in turn causes increased secretion of LH and increased production of androgens.73 Further, insulin can stimulate the ovaries to synthesize androgens by enhancing the activity of CYP17α and other steroidogenic enzymes.74 IR is negatively correlated with serum sex hormone globulin (SHBG),75 which binds androgens with high affinity,76 so IR can increase free androgen concentrations by reducing SHBG levels. HA and IR can exacerbate obesity,77,78 and obesity can exacerbate IR by affecting the PI3K pathway.79 Obesity can also exacerbate HA by affecting the abnormal function of the hypothalamic-pituitary-ovarian axis and the peripheral metabolism of sex hormones.80 Visceral adipose tissue can elicit an inflammatory response and maintain an inflammatory state by increasing the production of inflammatory cytokines, the production of monocyte chemoattractant proteins, and the recruitment of immune cells.81 Chronic low-grade inflammation may mediate the effects of sympathetic dysfunction on HA and IR.82 The interaction between risk factors further worsens the endocrine and metabolic disorders in patients with PCOS, leading to the development and progression of NAFLD.
Management of NAFLD in PCOS
There is no definitive approach to the management of NAFLD in PCOS. Current research on the management of NAFLD in PCOS is mainly focused on lifestyle modification, pharmacological treatments, and bariatric surgery.
Lifestyle modification are the basic treatment for PCOS and NAFLD.83,84 Lifestyle modification include a combination of diet control and increased exercise to achieve weight loss. Lifestyle modification can reduce weight, increase insulin sensitivity, and decrease hyperandrogenemia in women with PCOS;85–87 the harmful effects of endocrine and metabolic disorders on the livers of women with PCOS are also reduced. One study confirmed that weight loss through lifestyle modification significantly reduced the characteristics of NAFLD, with reduced liver inflammation observed in subjects who lost ≥5% of their body weight and regression of liver fibrosis observed in subjects who lost ≥10% of their body weight.88 Clinical studies have also shown improvements in liver function in PCOS with lifestyle modification. A 6-week, 8-hour restricted eating study in 18 women with anovulatory PCOS showed that restricted eating reduced body weight, decreased body fat, improved menstrual cycles and hyperandrogenemia, and reduced alanine aminotransferase (ALT) levels in women with PCOS.89
Although no drugs have been recommended for the treatment of NAFLD in PCOS, some drugs have been found in clinical studies to improve liver function and histology and to reduce lipid aggregation in PCOS.
Metformin has been used clinically for over 60 years and is also the first choice for the treatment of type 2 diabetes. Metformin acts by activating AMP-activated protein kinase (AMPK).90 Activated AMPK shifts the cell from an anabolic to a catabolic state, shutting down the synthetic pathway that consumes adenosine triphosphate and restoring energy balance. As a result, glucose, lipid and protein synthesis as well as cell growth are inhibited, while fatty acid oxidation and glucose uptake are stimulated.91 AMPK can mediate phosphorylation of target substrates,92 attenuating NAFLD through three pathways: inhibition of de novo lipid synthesis in the liver, increased oxidation of fatty acids in the liver, and promotion of mitochondrial function and integrity in adipose tissue.93 The application of metformin in PCOS has been confirmed. Overweight women with PCOS treated with metformin showed significant improvements in endocrine and metabolic markers, including testosterone, follicle-stimulating hormone, luteinizing hormone, and low-density lipoprotein cholesterol.94 Some studies also noted findings on the improvement of NAFLD in PCOS with metformin. A study that included 82 obese women with PCOS, who received metformin for 8 months, showed that metformin reduced the mean weight, serum ALT, and glutamyl transpeptidase (GGT) of these patients from 100.3 kg to 96.6 kg, 29.7 U/L to 25.8 U/L, and 21.4 U/L to 16.9 U/L, respectively.95 Another study of 140 young overweight patients with hyperinsulinemia and PCOS treated with metformin for 12 months showed a reduction in the prevalence of metabolic syndrome and liver involvement in these patients.96 Therefore, metformin has shown some improvement in NAFLD with PCOS, especially in overweight and obese women with PCOS and in women with hyperinsulinemia and PCOS.
Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors expressed in the liver, adipose tissue, heart, skeletal muscle, and kidney that are involved in the transcriptional regulation of key metabolic pathways, such as lipid metabolism, adipogenesis, and insulin sensitivity.97 Thiazolidinediones, as PPARγ agonists, have insulin-sensitizing effects and are widely used in the treatment of diabetes mellitus. Additionally, the role of thiazolidinedione in the treatment of NASH has been recognized. Pioglitazone alleviates NASH in diabetic and pre-diabetic patients, reduces liver fibrosis scores, lowers liver triglyceride levels from 19% to 7%, and improves hepatic insulin sensitivity.98 The same effect was observed with pioglitazone in non-diabetic patients with NASH, with improvements in ALT and GGT and a decrease in histological hepatocyte damage, Mallory-Denker vesicles, and fibrosis.99 Pioglitazone has also been shown to improve menstrual cycles and ovulation and to reduce glucose metabolism indicators in PCOS.74,100 However, the use of thiazolidinedione in PCOS is limited by its side effects on weight gain and cardiovascular aspects.101,102 Therefore, the application of thiazolidinedione to the treatment of NAFLD in non-obese patients with PCOS will probably have more positive results.
GLP1 Receptor Agonists
Incretin peptides are intestinal hormones that promote postprandial insulin secretion in a glucose-dependent manner, including glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and have effects on the regulation of islet hormone secretion, glucose concentration, lipid metabolism, intestinal motility, appetite, and body weight.103 By performing an oral glucose tolerance test on women with PCOS and healthy controls, it was detected that blood GLP1 concentrations at 180 minutes were significantly lower in women with PCOS than in healthy controls.104 Therefore, the use of GLP1 receptor agonists in PCOS is feasible. Liraglutide reduces body weight in overweight or obese women with PCOS,105 improves IR in women with PCOS,106 reduces free testosterone levels, elevates SHBG levels, and improves menstrual cycle and ovarian function in women with PCOS.107 The improvement of NAFLD in PCOS by liraglutide has also been clinically demonstrated. A double-blind, placebo-controlled, randomized clinical trial of women with PCOS treated with liraglutide for 26 weeks showed that liraglutide reduced liver fat content by 44%, visceral adipose tissue by 18%, and the prevalence of NAFLD by two-thirds in these patients.108 For NAFLD in obese patients with PCOS, liraglutide may provide additional beneficial effects.109
Spironolactone mainly acts as an antagonist binding to androgen receptors and can inhibit ovarian and adrenal steroid production as well as 5-alpha-reductase activity, thus exerting an anti-androgenic effect to achieve a therapeutic effect on PCOS.110,111 Clinical studies show that spironolactone can improve HA and hirsutism and restore menstrual cycles in PCOS.112,113 Spironolactone also reduces serum free fatty acid levels in PCOS.114 In a letrozole-induced rat model, spironolactone was observed to reduce uric acid and malondialdehyde in the liver, elevate glutathione reductase in the liver, reduce hepatic triglyceride accumulation, and alleviate NAFLD.115 However, spironolactone is often used in combination with oral contraceptives for the treatment of PCOS because it can cause irregular menstruation when used in high doses alone and has the risk of feminizing the male fetus in pregnant patients.110,111
Recent studies have shown that some nutritional supplements can be helpful in the treatment of NAFLD in PCOS. A 12-week combination of 1000 mg omega-3 fatty acids (containing 400 mg of α-linolenic acid) and 400 IU vitamin E supplementation in women with PCOS significantly improved IR index and reduced total and free testosterone.116 The combination also downregulated lipoprotein(a) and oxidized low-density lipoprotein (Ox-LDL) expression, reduced triglycerides and very low-density lipoproteins, and improved overall plasma antioxidant capacity.117 An 8-week supplementation of 4 g/d of omega-3 fatty acids and measurement of hepatic fat content by proton magnetic resonance spectroscopy in 25 women with PCOS showed that omega-3 fatty acids reduced liver fat by ≥5% in women with PCOS.118 In addition, vitamin E can also reduce hepatic steatosis, inhibit liver inflammation, and improve NAFLD by inhibiting lipid accumulation and peroxidation in the liver.119 Vitamin D supplementation of 3200 IU/d for 3 months in 40 patients with PCOS showed that vitamin D reduced ALT levels in PCOS patients, and a downward trend was observed for hyaluronic acid, type III procollagen N-terminal pro-peptide, and enhanced liver fibrosis (ELF) scores.120 Although some clinical studies have observed the therapeutic effect of nutritional supplements on NAFLD in PCOS, there is still no evidence that they can be used alone in the treatment of PCOS, and additional clinical studies are needed to confirm their therapeutic value in PCOS.
Bariatric surgery has proven valuable in the treatment of obese women with PCOS. Bariatric surgery can improve menstrual abnormalities, restore ovarian morphology, improve HA and hirsutism, reduce body weight, and improve glucose metabolism and dyslipidemia in obese patients with PCOS.121–123 In addition, clinical studies have confirmed that bariatric surgery can significantly reduce ALT and aspartate aminotransferase (AST) levels in women with PCOS.124 However, more studies are needed to further confirm the effects of bariatric surgery on hepatic lipid metabolism and hepatic histological improvement in women with PCOS.
There is growing evidence that PCOS can increase the prevalence of NAFLD, mainly associated with HA and IR. Therefore, screening for NAFLD should be enhanced in patients with PCOS, especially those with HA and IR features. Although there is no clear protocol for the treatment of NAFLD in PCOS, it appears that lifestyle modification should be the basis, and drugs to improve metabolism represented by insulin sensitizers and GLP1 receptor agonists may have positive application prospects.
This work was supported by a grant from the National Natural Science Foundation of China (grant number 81570765).
The authors declare no conflicts of interest in this work.
1. Ganie MA, Vasudevan V, Wani IA, et al. Epidemiology, pathogenesis, genetics & management of polycystic ovary syndrome in India. Indian J Med Res. 2019;150(4):333–344. doi:10.4103/ijmr.IJMR_1937_17
2. Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018;14(5):270–284. doi:10.1038/nrendo.2018.24
3. Zawadzki JK. Dunaif A.Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, editors. Polycystic Ovary Syndrome. Boston: Blackwell Scientific; 1992:377–384.
4. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19–25. doi:10.1016/j.fertnstert.2003.10.004
5. Azziz R, Carmina E, Dewailly D, et al.; Androgen Excess Society. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab. 2006;91(11):4237–4245. doi:10.1210/jc.2006-0178.
6. Lizneva D, Suturina L, Walker W, et al. Criteria, prevalence, and phenotypes of polycystic ovary syndrome. Fertil Steril. 2016;106(1):6–15. doi:10.1016/j.fertnstert.2016.05.003
7. Lentscher JA, Decherney AH. Clinical Presentation and Diagnosis of Polycystic Ovarian Syndrome. Clin Obstet Gynecol. 2021;64(1):3–11. doi:10.1097/GRF.0000000000000563
8. Zeng X, Xie YJ, Liu YT, et al. Polycystic ovarian syndrome: correlation between hyperandrogenism, insulin resistance and obesity. Clin Chim Acta. 2020;502:214–221. doi:10.1016/j.cca.2019.11.003
9. Berni TR, Morgan CL, Rees DA. Women With Polycystic Ovary Syndrome Have an Increased Risk of Major Cardiovascular Events: a Population Study. J Clin Endocrinol Metab. 2021;106(9):e3369–e3380. doi:10.1210/clinem/dgab392
10. Wang Y, Ni Z, Li K. The prevalence of anxiety and depression of different severity in women with polycystic ovary syndrome: a meta-analysis. Gynecol Endocrinol. 2021;37(12):1072–1078. doi:10.1080/09513590.2021.1942452
11. Enechukwu CI, Onuegbu AJ, Olisekodiaka MJ, et al. Oxidative stress markers and lipid profiles of patients with polycystic ovary syndrome in a Nigerian tertiary hospital. Obstet Gynecol Sci. 2019;62(5):335–343. doi:10.5468/ogs.2019.62.5.335
12. Meczekalski B, Pérez-Roncero GR, López-Baena MT, et al. The polycystic ovary syndrome and gynecological cancer risk. Gynecol Endocrinol. 2020;36(4):289–293. doi:10.1080/09513590.2020.1730794
13. Perumpail BJ, Khan MA, Yoo ER, et al. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J Gastroenterol. 2017;23(47):8263–8276. doi:10.3748/wjg.v23.i47.8263
14. Cardoso AC, de Figueiredo-Mendes C. Current management of NAFLD/NASH. Liver Int. 2021;41 Suppl 1:89–94. doi:10.1111/liv.14869
15. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. doi:10.1002/hep.28431
16. Younossi Z, Anstee QM, Marietti M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15(1):11–20. doi:10.1038/nrgastro.2017.109
17. Brown AJ, Tendler DA, McMurray RG, Setji TL. Polycystic ovary syndrome and severe nonalcoholic steatohepatitis: beneficial effect of modest weight loss and exercise on liver biopsy findings. Endocr Pract. 2005;11(5):319–324. doi:10.4158/EP.11.5.319
18. Setji TL, Holland ND, Sanders LL, et al. Nonalcoholic steatohepatitis and nonalcoholic Fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91(5):1741–1747. doi:10.1210/jc.2005-2774
19. Gambarin-Gelwan M, Kinkhabwala SV, Schiano TD, et al. Prevalence of nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Clin Gastroenterol Hepatol. 2007;5(4):496–501. doi:10.1016/j.cgh.2006.10.010
20. Cerda C, Pérez-Ayuso RM, Riquelme A, et al. Nonalcoholic fatty liver disease in women with polycystic ovary syndrome. J Hepatol. 2007;47(3):412–417. doi:10.1016/j.jhep.2007.04.012
21. Vassilatou E, Lafoyianni S, Vryonidou A, et al. Increased androgen bioavailability is associated with non-alcoholic fatty liver disease in women with polycystic ovary syndrome. Hum Reprod. 2010;25(1):212–220. doi:10.1093/humrep/dep380
22. Tan S, Bechmann LP, Benson S, et al. Apoptotic markers indicate nonalcoholic steatohepatitis in polycystic ovary syndrome. J Clin Endocrinol Metab. 2010;95(1):343–348. doi:10.1210/jc.2009-1834
23. Hossain N, Stepanova M, Afendy A, et al. Non-alcoholic steatohepatitis (NASH) in patients with polycystic ovarian syndrome (PCOS). Scand J Gastroenterol. 2011;46(4):479–484. doi:10.3109/00365521.2010.539251
24. Zueff LF, Martins WP, Vieira CS, Ferriani RA. Ultrasonographic and laboratory markers of metabolic and cardiovascular disease risk in obese women with polycystic ovary syndrome. Ultrasound Obstet Gynecol. 2012;39(3):341–347. doi:10.1002/uog.10084
25. Karoli R, Fatima J, Chandra A, et al. Prevalence of hepatic steatosis in women with polycystic ovary syndrome. J Hum Reprod Sci. 2013;6(1):9–14. doi:10.4103/0974-1208.112370
26. Qu Z, Zhu Y, Jiang J, Shi Y, Chen Z. The clinical characteristics and etiological study of nonalcoholic fatty liver disease in Chinese women with PCOS. Iran J Reprod Med. 2013;11(9):725–732.
27. Bohdanowicz-Pawlak A, Lenarcik-Kabza A, Brona A, et al. Non-alcoholic fatty liver disease in women with polycystic ovary syndrome - clinical and metabolic aspects and lipoprotein lipase gene polymorphism. Endokrynol Pol. 2014;65(6):416–421. doi:10.5603/EP.2014.0058
28. Romanowski MD, Parolin MB, Freitas AC, et al. Prevalence of non-alcoholic fatty liver disease in women with polycystic ovary syndrome and its correlation with metabolic syndrome. Arq Gastroenterol. 2015;52(2):117–123. doi:10.1590/S0004-28032015000200008
29. Macut D, Tziomalos K, Božić-Antić I, et al. Non-alcoholic fatty liver disease is associated with insulin resistance and lipid accumulation product in women with polycystic ovary syndrome. Hum Reprod. 2016;31(6):1347–1353. doi:10.1093/humrep/dew076
30. Cai J, Wu CH, Zhang Y, et al. High-free androgen index is associated with increased risk of non-alcoholic fatty liver disease in women with polycystic ovary syndrome, independent of obesity and insulin resistance. Int J Obes. 2017;41(9):1341–1347. doi:10.1038/ijo.2017.116
31. Mehrabian F, Jahanmardi R. Nonalcoholic Fatty Liver Disease in a Sample of Iranian Women with Polycystic Ovary Syndrome. Int J Prev Med. 2017;8:79. doi:10.4103/ijpvm.IJPVM_305_16
32. Petta S, Ciresi A, Bianco J, et al. Insulin resistance and hyperandrogenism drive steatosis and fibrosis risk in young females with PCOS. PLoS One. 2017;12(11):e0186136. doi:10.1371/journal.pone.0186136
33. Zhang J, Hu J, Zhang C, et al. Analyses of risk factors for polycystic ovary syndrome complicated with non-alcoholic fatty liver disease. Exp Ther Med. 2018;15(5):4259–4264. doi:10.3892/etm.2018.5932
34. Harsha Varma S, Tirupati S, Pradeep TVS, et al. Insulin resistance and hyperandrogenemia independently predict nonalcoholic fatty liver disease in women with polycystic ovary syndrome. Diabetes Metab Syndr. 2019;13(2):1065–1069. doi:10.1016/j.dsx.2018.12.020
35. Salva-Pastor N, López-Sánchez GN, Chávez-Tapia NC, et al. Polycystic ovary syndrome with feasible equivalence to overweight as a risk factor for non-alcoholic fatty liver disease development and severity in Mexican population. Ann Hepatol. 2020;19(3):251–257. doi:10.1016/j.aohep.2020.01.004
36. Chakraborty S, Ganie MA, Masoodi I, et al. Fibroscan as a non-invasive predictor of hepatic steatosis in women with polycystic ovary syndrome. Indian J Med Res. 2020;151(4):333–341. doi:10.4103/ijmr.IJMR_610_18
37. Taranto DOL, Guimarães TCM, Couto CA, et al. Nonalcoholic fatty liver disease in women with polycystic ovary syndrome: associated factors and noninvasive fibrosis staging in a single Brazilian center. Arch Endocrinol Metab. 2020;64(3):235–242. doi:10.20945/2359-3997000000242
38. Shengir M, Krishnamurthy S, Ghali P, et al. Prevalence and predictors of nonalcoholic fatty liver disease in South Asian women with polycystic ovary syndrome. World J Gastroenterol. 2020;26(44):7046–7060. doi:10.3748/wjg.v26.i44.7046
39. Sarkar M, Terrault N, Chan W, et al. Polycystic ovary syndrome (PCOS) is associated with NASH severity and advanced fibrosis. Liver Int. 2020;40(2):355–359. doi:10.1111/liv.14279
40. McCartney CR, Campbell RE. Abnormal GnRH Pulsatility in Polycystic Ovary Syndrome: recent Insights. Curr Opin Endocr Metab Res. 2020;12:78–84. doi:10.1016/j.coemr.2020.04.005
41. Jones H, Sprung VS, Pugh CJ, et al. Polycystic ovary syndrome with hyperandrogenism is characterized by an increased risk of hepatic steatosis compared to nonhyperandrogenic PCOS phenotypes and healthy controls, independent of obesity and insulin resistance. J Clin Endocrinol Metab. 2012;97(10):3709–3716. doi:10.1210/jc.2012-1382
42. Seidu T, McWhorter P, Myer J, et al. DHT causes liver steatosis via transcriptional regulation of SCAP in normal weight female mice. J Endocrinol. 2021;250(2):49–65. doi:10.1530/JOE-21-0040
43. Cui P, Hu W, Ma T, et al. Long-term androgen excess induces insulin resistance and non-alcoholic fatty liver disease in PCOS-like rats. J Steroid Biochem Mol Biol. 2021;208:105829. doi:10.1016/j.jsbmb.2021.105829
44. Li T, Zhang T, Cui T, et al. Involvement of endogenous testosterone in hepatic steatosis in women with polycystic ovarian syndrome. J Steroid Biochem Mol Biol. 2020;204:105752. doi:10.1016/j.jsbmb.2020.105752
45. Anzai Á, Marcondes RR, Gonçalves TH, et al. Impaired branched-chain amino acid metabolism may underlie the nonalcoholic fatty liver disease-like pathology of neonatal testosterone-treated female rats. Sci Rep. 2017;7(1):13167. doi:10.1038/s41598-017-13451-8
46. Zhang Y, Meng F, Sun X, et al. Hyperandrogenism and insulin resistance contribute to hepatic steatosis and inflammation in female rat liver. Oncotarget. 2018;9(26):18180–18197. doi:10.18632/oncotarget.2447
47. Jahromi BN, Borzou N, Parsanezhad ME, et al. Associations of insulin resistance, sex hormone-binding globulin, triglyceride, and hormonal profiles in polycystic ovary syndrome: a cross-sectional study. Int J Reprod Biomed. 2021;19(7):653–662. doi:10.18502/ijrm.v19i7.9476
48. Welt CK, Duran JM. Genetics of polycystic ovary syndrome. Semin Reprod Med. 2014;32(3):177–182. doi:10.1055/s-0034-1371089
49. Pauli JM, Raja-Khan N, Wu X, Legro RS. Current perspectives of insulin resistance and polycystic ovary syndrome. Diabet Med. 2011;28(12):1445–1454. doi:10.1111/j.1464-5491.2011.03460.x
50. Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism. 2016;65(8):1038–1048. doi:10.1016/j.metabol.2015.12.012
51. Kawano Y, Cohen DE. Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J Gastroenterol. 2013;48(4):434–441. doi:10.1007/s00535-013-0758-5
52. Peverill W, Powell LW, Skoien R. Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci. 2014;15(5):8591–8638. doi:10.3390/ijms15058591
53. Fujii H, Kawada N, Japan Study Group Of Nafld Jsg-Nafld. The Role of Insulin Resistance and Diabetes in Nonalcoholic Fatty Liver Disease. Int J Mol Sci. 2020;21(11):3863. doi:10.3390/ijms21113863
54. O’Reilly MW, House PJ, Tomlinson JW. Understanding androgen action in adipose tissue. J Steroid Biochem Mol Biol. 2014;143:277–284. doi:10.1016/j.jsbmb.2014.04.008
55. Barber TM, Hanson P, Weickert MO, Franks S. Obesity and Polycystic Ovary Syndrome: implications for Pathogenesis and Novel Management Strategies. Clin Med Insights Reprod Health. 2019;13:1179558119874042. doi:10.1177/1179558119874042
56. Shengir M, Chen T, Guadagno E, et al. Non-alcoholic fatty liver disease in premenopausal women with polycystic ovary syndrome: a systematic review and meta-analysis. JGH Open. 2021;5(4):434–445. doi:10.1002/jgh3.12512
57. Hu W, Li L, Yang M, et al. Circulating Sfrp5 is a signature of obesity-related metabolic disorders and is regulated by glucose and liraglutide in humans. J Clin Endocrinol Metab. 2013;98(1):290–298. doi:10.1210/jc.2012-2466
58. Wang GX, Zhao XY, Meng ZX, et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat Med. 2014;20(12):1436–1443. doi:10.1038/nm.3713
59. Polyzos SA, Kountouras J, Mantzoros CS. Obesity and nonalcoholic fatty liver disease: from pathophysiology to therapeutics. Metabolism. 2019;92:82–97. doi:10.1016/j.metabol.2018.11.014
60. Polyzos SA, Kountouras J, Mantzoros CS. Adipose tissue, obesity and non-alcoholic fatty liver disease. Minerva Endocrinol. 2017;42(2):92–108. doi:10.23736/S0391-1977.16.02563-3
61. Rudnicka E, Kunicki M, Suchta K, et al. Inflammatory Markers in Women with Polycystic Ovary Syndrome. Biomed Res Int. 2020;2020:4092470. doi:10.1155/2020/4092470
62. Spritzer PM, Lecke SB, Satler F, Morsch DM. Adipose tissue dysfunction, adipokines, and low-grade chronic inflammation in polycystic ovary syndrome. Reproduction. 2015;149(5):R219–R227. doi:10.1530/REP-14-0435
63. Appari M, Channon KM, McNeill E. Metabolic Regulation of Adipose Tissue Macrophage Function in Obesity and Diabetes. Antioxid Redox Signal. 2018;29(3):297–312. doi:10.1089/ars.2017.7060
64. Vonghia L, Magrone T, Verrijken A, et al. Peripheral and Hepatic Vein Cytokine Levels in Correlation with Non-Alcoholic Fatty Liver Disease (NAFLD)-Related Metabolic, Histological, and Haemodynamic Features. PLoS One. 2015;10(11):e0143380. doi:10.1371/journal.pone.0143380
65. Polyzos SA, Kountouras J, Mantzoros CS. Adipokines in nonalcoholic fatty liver disease. Metabolism. 2016;65(8):1062–1079. doi:10.1016/j.metabol.2015.11.006
66. Krishnan A, Muthusami S, Periyasamy L, et al. Effect of DHT-Induced Hyperandrogenism on the Pro-Inflammatory Cytokines in a Rat Model of Polycystic Ovary Morphology. Medicina (Kaunas). 2020;56(3):100. doi:10.3390/medicina56030100
67. Kuliczkowska Plaksej J, Laczmanski L, Milewicz A, et al. Cannabinoid receptor 1 gene polymorphisms and nonalcoholic Fatty liver disease in women with polycystic ovary syndrome and in healthy controls. Int J Endocrinol. 2014;2014:232975. doi:10.1155/2014/232975
68. Baranova A, Tran TP, Afendy A, et al. Molecular signature of adipose tissue in patients with both non-alcoholic fatty liver disease (NAFLD) and polycystic ovarian syndrome (PCOS). J Transl Med. 2013;11:133. doi:10.1186/1479-5876-11-133
69. Bohdanowicz-Pawlak A, Lenarcik-Kabza A, Brona A, et al. Non-alcoholic fatty liver disease in women with polycystic ovary syndrome - clinical and metabolic aspects and lipoprotein lipase gene polymorphism. Endokrynol Pol. 2014;65(6):416. doi:10.5603/EP.2014.0058
70. Song X, Shen Q, Fan L, et al. Dehydroepiandrosterone-induced activation of mTORC1 and inhibition of autophagy contribute to skeletal muscle insulin resistance in a mouse model of polycystic ovary syndrome. Oncotarget. 2018;9(15):11905–11921. doi:10.18632/oncotarget.24190
71. Corbould A, Kim YB, Youngren JF, et al. Insulin resistance in the skeletal muscle of women with PCOS involves intrinsic and acquired defects in insulin signaling. Am J Physiol Endocrinol Metab. 2005;288(5):E1047–E1054. doi:10.1152/ajpendo.00361.2004
72. Dunaif A, Xia J, Book CB, et al. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest. 1995;96(2):801–810. doi:10.1172/JCI118126
73. Adashi EY, Hsueh AJ, Yen SS. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology. 1981;108(4):1441–1449. doi:10.1210/endo-108-4-1441
74. Pani A, Gironi I, Di Vieste G, et al. From Prediabetes to Type 2 Diabetes Mellitus in Women with Polycystic Ovary Syndrome: lifestyle and Pharmacological Management. Int J Endocrinol. 2020;2020:6276187. doi:10.1155/2020/6276187
75. Biernacka-Bartnik A, Kocełak P, Owczarek AJ, et al. Prediction of Insulin Resistance and Impaired Fasting Glucose Based on Sex Hormone-Binding Globulin (SHBG) Levels in Polycystic Ovary Syndrome. Int J Endocrinol. 2022;2022:6498768. doi:10.1155/2022/6498768
76. Laurent MR, Hammond GL, Blokland M, et al. Sex hormone-binding globulin regulation of androgen bioactivity in vivo: validation of the free hormone hypothesis. Sci Rep. 2016;6:35539. doi:10.1038/srep35539
77. Karabulut A, Yaylali GF, Demirlenk S, et al. Evaluation of body fat distribution in PCOS and its association with carotid atherosclerosis and insulin resistance. Gynecol Endocrinol. 2012;28(2):111–114. doi:10.3109/09513590.2011.589929
78. Torres Fernandez ED, Adams KV, Syed M, et al. Long-Lasting Androgen-Induced Cardiometabolic Effects in Polycystic Ovary Syndrome. J Endocr Soc. 2018;2(8):949–964. doi:10.1210/js.2018-00131
79. Barber TM, Kyrou I, Randeva HS, Weickert MO. Mechanisms of Insulin Resistance at the Crossroad of Obesity with Associated Metabolic Abnormalities and Cognitive Dysfunction. Int J Mol Sci. 2021;22(2):546. doi:10.3390/ijms22020546
80. Legro RS. Obesity and PCOS: implications for diagnosis and treatment. Semin Reprod Med. 2012;30(6):496–506. doi:10.1055/s-0032-1328878
81. Rostamtabar M, Esmaeilzadeh S, Tourani M, et al. Pathophysiological roles of chronic low-grade inflammation mediators in polycystic ovary syndrome. J Cell Physiol. 2021;236(2):824–838. doi:10.1002/jcp.29912
82. Shorakae S, Ranasinha S, Abell S, et al. Inter-related effects of insulin resistance, hyperandrogenism, sympathetic dysfunction and chronic inflammation in PCOS. Clin Endocrinol. 2018;89(5):628–633. doi:10.1111/cen.13808
83. Rocha AL, Oliveira FR, Azevedo RC, et al. Recent advances in the understanding and management of polycystic ovary syndrome. F1000Res. 2019;8:565. doi:10.12688/f1000research.15318.1
84. Mundi MS, Velapati S, Patel J, et al. Evolution of NAFLD and Its Management. Nutr Clin Pract. 2020;35(1):72–84. doi:10.1002/ncp.10449
85. Shele G, Genkil J, Speelman D, Systematic A. Review of the Effects of Exercise on Hormones in Women with Polycystic Ovary Syndrome. J Funct Morphol Kinesiol. 2020;5(2):35. doi:10.3390/jfmk5020035
86. Lim SS, Hutchison SK, Van Ryswyk E, et al. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database Syst Rev. 2019;3(3):CD007506. doi:10.1002/14651858.CD007506.pub4
87. Abdolahian S, Tehrani FR, Amiri M, et al. Effect of lifestyle modifications on anthropometric, clinical, and biochemical parameters in adolescent girls with polycystic ovary syndrome: a systematic review and meta-analysis. BMC Endocr Disord. 2020;20(1):71. doi:10.1186/s12902-020-00552-1
88. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015;149(2):367–378.e5. doi:10.1053/j.gastro.2015.04.005
89. Li C, Xing C, Zhang J, et al. Eight-hour time-restricted feeding improves endocrine and metabolic profiles in women with anovulatory polycystic ovary syndrome. J Transl Med. 2021;19(1):148. doi:10.1186/s12967-021-02817-2
90. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–1174. doi:10.1172/JCI13505
91. Viollet B, Guigas B, Sanz Garcia N, et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253–270. doi:10.1042/CS20110386
92. Steinberg GR, Kemp BE. AMPK in Health and Disease. Physiol Rev. 2009;89(3):1025–1078. doi:10.1152/physrev.00011.2008
93. Smith BK, Marcinko K, Desjardins EM, et al. Treatment of nonalcoholic fatty liver disease: role of AMPK. Am J Physiol Endocrinol Metab. 2016;311(4):E730–E740. doi:10.1152/ajpendo.00225.2016
94. Guan Y, Wang D, Bu H, et al. The Effect of Metformin on Polycystic Ovary Syndrome in Overweight Women: a Systematic Review and Meta-Analysis of Randomized Controlled Trials. Int J Endocrinol. 2020;2020:5150684. doi:10.1155/2020/5150684
95. Preiss D, Sattar N, Harborne L, et al. The effects of 8 months of metformin on circulating GGT and ALT levels in obese women with polycystic ovarian syndrome. Int J Clin Pract. 2008;62(9):1337–1343. doi:10.1111/j.1742-1241.2008.01825.x
96. Gangale MF, Miele L, Lanzone A, et al. Long-term metformin treatment is able to reduce the prevalence of metabolic syndrome and its hepatic involvement in young hyperinsulinaemic overweight patients with polycystic ovarian syndrome. Clin Endocrinol. 2011;75(4):520–527. doi:10.1111/j.1365-2265.2011.04093.x
97. Brown JD, Plutzky J. Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. Circulation. 2007;115(4):518–533. doi:10.1161/CIRCULATIONAHA.104.475673
98. Cusi K, Orsak B, Bril F, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: a Randomized Trial. Ann Intern Med. 2016;165(5):305–315. doi:10.7326/M15-1774
99. Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135(4):1176–1184. doi:10.1053/j.gastro.2008.06.047
100. Xu Y, Wu Y, Huang Q. Comparison of the effect between pioglitazone and metformin in treating patients with PCOS: a meta-analysis. Arch Gynecol Obstet. 2017;296(4):661–677. doi:10.1007/s00404-017-4480-z
101. Mahady SE, Webster AC, Walker S, et al. The role of thiazolidinediones in non-alcoholic steatohepatitis - a systematic review and meta analysis. J Hepatol. 2011;55(6):1383–1390. doi:10.1016/j.jhep.2011.03.016
102. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298(10):1180–1188. doi:10.1001/jama.298.10.1180
103. Campbell JE, Drucker DJ. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 2013;17(6):819–837. doi:10.1016/j.cmet.2013.04.008
104. Vrbikova J, Hill M, Bendlova B, et al. Incretin levels in polycystic ovary syndrome. Eur J Endocrinol. 2008;159(2):121–127. doi:10.1530/EJE-08-0097
105. Rasmussen CB, Lindenberg S. The effect of liraglutide on weight loss in women with polycystic ovary syndrome: an observational study. Front Endocrinol (Lausanne). 2014;5:140. doi:10.3389/fendo.2014.00140
106. Tian D, Chen W, Xu Q, et al. Liraglutide monotherapy and add on therapy on obese women with polycystic ovarian syndromes: a systematic review and meta-analysis. Minerva Med. 2021. doi:10.23736/S0026-4806.21.07085-3
107. Nylander M, Frøssing S, Clausen HV, et al. Effects of liraglutide on ovarian dysfunction in polycystic ovary syndrome: a randomized clinical trial. Reprod Biomed Online. 2017l;35(1):121–127. doi:10.1016/j.rbmo.2017.03.023
108. Frøssing S, Nylander M, Chabanova E, et al. Effect of liraglutide on ectopic fat in polycystic ovary syndrome: a randomized clinical trial. Diabetes Obes Metab. 2018;20(1):215–218. doi:10.1111/dom.13053
109. Kahal H, Abouda G, Rigby AS, et al. Glucagon-like peptide-1 analogue, liraglutide, improves liver fibrosis markers in obese women with polycystic ovary syndrome and nonalcoholic fatty liver disease. Clin Endocrinol. 2014;81(4):523–528. doi:10.1111/cen.12369
110. Badawy A, Elnashar A. Treatment options for polycystic ovary syndrome. Int J Womens Health. 2011;3:25–35. doi:10.2147/IJWH.S11304
111. Sirmans SM, Pate KA. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin Epidemiol. 2013;6:1–13. doi:10.2147/CLEP.S37559
112. Mazza A, Fruci B, Guzzi P, et al. In PCOS patients the addition of low-dose spironolactone induces a more marked reduction of clinical and biochemical hyperandrogenism than metformin alone. Nutr Metab Cardiovasc Dis. 2014;24(2):132–139. doi:10.1016/j.numecd.2013.04.016
113. Diri H, Karaburgu S, Acmaz B, et al. Comparison of spironolactone and spironolactone plus metformin in the treatment of polycystic ovary syndrome. Gynecol Endocrinol. 2016;32(1):42–45. doi:10.3109/09513590.2015.1080679
114. Muneyyirci-Delale O, Kaplan J, Joulak I, et al. Serum free fatty acid levels in PCOS patients treated with glucophage, magnesium oxide and spironolactone. Gynecol Endocrinol. 2013;29(5):474–477. doi:10.3109/09513590.2013.769515
115. Adeyanju OA, Falodun TO, Michael OS, et al. Spironolactone reversed hepato-ovarian triglyceride accumulation caused by letrozole-induced polycystic ovarian syndrome: tissue uric acid-a familiar foe. Naunyn Schmiedebergs Arch Pharmacol. 2020;393(6):1055–1066. doi:10.1007/s00210-020-01809-1
116. Ebrahimi FA, Samimi M, Foroozanfard F, et al. The Effects of Omega-3 Fatty Acids and Vitamin E Co-Supplementation on Indices of Insulin Resistance and Hormonal Parameters in Patients with Polycystic Ovary Syndrome: a Randomized, Double-Blind, Placebo-Controlled Trial. Exp Clin Endocrinol Diabetes. 2017;125(6):353–359. doi:10.1055/s-0042-117773
117. Rahmani E, Samimi M, Ebrahimi FA, et al. The effects of omega-3 fatty acids and vitamin E co-supplementation on gene expression of lipoprotein(a) and oxidized low-density lipoprotein, lipid profiles and biomarkers of oxidative stress in patients with polycystic ovary syndrome. Mol Cell Endocrinol. 2017;439:247–255. doi:10.1016/j.mce.2016.09.008
118. Cussons AJ, Watts GF, Mori TA, Stuckey BG. Omega-3 fatty acid supplementation decreases liver fat content in polycystic ovary syndrome: a randomized controlled trial employing proton magnetic resonance spectroscopy. J Clin Endocrinol Metab. 2009;94(10):3842–3848. doi:10.1210/jc.2009-0870
119. Nagashimada M, Ota T. Role of vitamin E in nonalcoholic fatty liver disease. IUBMB Life. 2019;71(4):516–522. doi:10.1002/iub.1991
120. Javed Z, Papageorgiou M, Deshmukh H, et al. A Randomized, Controlled Trial of Vitamin D Supplementation on Cardiovascular Risk Factors, Hormones, and Liver Markers in Women with Polycystic Ovary Syndrome. Nutrients. 2019;11(1):188. doi:10.3390/nu11010188
121. Ezzat RS, Abdallah W, Elsayed M, et al. Impact of bariatric surgery on androgen profile and ovarian volume in obese polycystic ovary syndrome patients with infertility. Saudi J Biol Sci. 2021;28(9):5048–5052. doi:10.1016/j.sjbs.2021.05.022
122. Christ JP, Falcone T. Bariatric Surgery Improves Hyperandrogenism, Menstrual Irregularities, and Metabolic Dysfunction Among Women with Polycystic Ovary Syndrome (PCOS). Obes Surg. 2018;28(8):2171–2177. doi:10.1007/s11695-018-3155-6
123. Li YJ, Han Y, He B. Effects of bariatric surgery on obese polycystic ovary syndrome: a systematic review and meta-analysis. Surg Obes Relat Dis. 2019;15(6):942–950. doi:10.1016/j.soard.2019.03.032
124. Gomez-Meade CA, Lopez-Mitnik G, Messiah SE, et al. Cardiometabolic health among gastric bypass surgery patients with polycystic ovarian syndrome. World J Diabetes. 2013;4(3):64–69. doi:10.4239/wjd.v4.i3.64
© 2022 The Author(s). This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.