Focusing on the metabolic phenotype of PCOS
Polycystic Ovarian Syndrome (PCOS) is one of the most common endocrine disorders that affects women of reproductive age and is characterized by hyperandrogenism, menstrual irregularity, and polycystic ovaries.1 PCOS is a multi-faceted disease, and although its pathophysiology is not clear, it includes increased ovarian steroid hormone production, defective insulin signaling, as well as genetic and environmental factors.2 Besides the well-defined reproductive phenotype, it is now widely recognized that PCOS also displays a metabolic phenotype.1 As a result, the clinical features reflect the heterogenous basis of the disease. The symptoms include hyperandrogenism, menstrual irregularity, polycystic ovaries, chronic anovulation, but also insulin resistance, glucose intolerance, and dyslipidemia.
Metabolic syndrome (MetS) is a cluster of different disease states, such as hypertension, type 2 diabetes, obesity, and dyslipidemia, which are highly associated with PCOS. In the United States, obesity affects 80% of women with PCOS, which corresponds with the rise of the obesity epidemic.3 Although it is unclear whether obesity causes PCOS, it can exacerbate the clinical features of the disease, particularly those related to MetS.3 Decreased insulin sensitivity is a hallmark of PCOS, ever since studies have reported post-receptor binding defects in insulin signaling consisting of increased serine phosphorylation of the insulin receptor and downstream molecules, such as insulin receptor substrate-1 (IRS-1) in women with PCOS.4,5 The decreased insulin sensitivity (or insulin resistance) leads to decreased uptake of glucose in target tissues, and failure of insulin to adequately suppress hepatic gluconeogenesis.1
As a result, insulin resistance increases the risk of impaired glucose tolerance and type 2 diabetes in women with PCOS. Research has shown that the prevalence of impaired glucose tolerance is 25-35% and that of type 2 diabetes is 4-10% in women with PCOS.6,7 In addition, women with PCOS have impaired pancreatic β-cell function, leading to decreased glucose-stimulated insulin secretion.6,8 It is now widely accepted that β-cell dysfunction, in addition to insulin resistance, are two of the most important pathophysiologies leading to the development of type 2 diabetes. Obesity plays a role in the metabolic dysfunctions of PCOS, however; insulin resistance, impaired glucose tolerance, and type 2 diabetes can occur independent of obesity, as reported in lean women with PCOS.1 Due to these metabolic imbalances, women with PCOS may also be at an increased risk for cardiovascular disease (CVD), although it is unclear whether PCOS independently increases risk of cardiovascular mortality.9 Indeed, PCOS is associated with dyslipidemia, an important risk factor for atherosclerotic cardiovascular disease (ASCVD), independent of age and body mass index.10,11
Despite metabolic abnormalities, the three current diagnostic criteria for PCOS, established by the National Institutes of Health (NIH), the Androgen Excess and PCOS Society, and the Rotterdam conference, do not incorporate the manifestations of the metabolic phenotype.12 This has led to underutilization of metabolic screening, ambiguity about which screening tools to use to assess metabolic dysfunction in PCOS, and lack of uniformity in screening practices among different physician specialties that treat PCOS.13,14 A recent survey from the American College of Obstetricians and Gynecologists (ACOG) reported that less than 20% of physicians screen women with PCOS for diabetes and dyslipidemia.13 Other studies have shown that about 26% of primary care physicians don’t screen for type 2 diabetes in women with PCOS, although this number is much lower for endocrinologists.15 Consensus statements from many professional societies, such as the Endocrine Society, the Androgen Excess and PCOS Society (AEPCOS), and the Australian PCOS Alliance guidelines, recommend screening for type 2 diabetes of all women with PCOS.16 Most of these recommendations, including the latest provided by the American Association of Clinical Endocrinologist (AACE), American College of Endocrinologist and AE-PCOS Society suggest the use of a 2-hr oral glucose tolerance test (OGTT).16 However, discrepancies still exist about how often to repeat OGTT, how to identify women with PCOS at high-risk for type 2 diabetes, and what test to use to evaluate insulin resistance.1,16 Additionally, questions remain on whether common methods used in clinical practice to assess glucose homeostasis or insulin resistance (such as glycated hemoglobin (HbA1c), fasting blood glucose, fasting insulin, and surrogate measures derived from OGTT) are relevant in PCOS.1,14
Due to the accumulating evidence of the increased metabolic risks and other multi-faceted interactions in PCOS, in 2012, an expert panel sponsored by the National Institutes of Health (NIH) concluded that it is time to give the condition a different name.17 This name would not necessarily focus on one single diagnostic criterion (such as polycystic ovaries), but would encompass the many metabolic, hypothalamus-pituitary-adrenal (HPA), and ovarian interactions in PCOS, and properly reflect the progress of the field.17 Experts have suggested the name “Metabolic Reproductive Syndrome”, although a consensus about the formal name change has not yet been reached in the medical community.12
Reducing cardiometabolic risk in PCOS
Lifestyle interventions, such as exercise and eating a balanced diet, are considered the first line to control cardiometabolic risk in PCOS, particularly in overweight and obese women. Since obesity is known to exacerbate both the reproductive and metabolic phenotypes of PCOS, lifestyle interventions can control symptoms by decreasing weight.18 In addition to diet and exercise, weight loss achieved by bariatric surgery has been shown to ameliorate the adverse metabolic profile in women with PCOS.19
Insulin resistance plays a pivotal role in PCOS, and the use of insulin sensitizers can be beneficial in decreasing cardiometabolic risk. Metformin, an oral oral-antidiabetic drug that decreases hepatic glucose production and improves insulin sensitivity, has been shown to improve glucose intolerance, insulin resistance, and hyperinsulinemia in women with PCOS, and is recommended in these women who have type 2 diabetes or impaired glucose tolerance.2,18 The use of other insulin sensitizers, such as thiazolidinediones (TZDs) and inositols, is not recommended due lack of efficacy and safety.18 In addition, newer anti-hyperglycemic agents have been evaluated in PCOS. Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RAs) potentiate the effects of endogenous GLP-1, an incretin hormone that is secreted following a meal bolus. Effects of GLP-1 RAs include stimulation of insulin secretion and inhibition of glucagon release when hyperglycemia is present, delay of gastric emptying, reduction of food intake with associated weight loss, and reduction of fasting and postprandial glucose.20 A study showed that the combination therapy of the GLP-1 RA liraglutide and metformin improved glucose tolerance and insulin resistance in women with PCOS compared to monotherapy, in addition to more weight loss.20 Dipeptidyl peptidase 4 (DPP-4) inhibitors increase the levels of incretins and consequently glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells.21 Since there is decreased β-cell function in PCOS, these agents may improve insulin secretion. Indeed, studies with DDP- 4 inhibitors alogliptin and sitagliptin have been shown to increase GSIS in women with PCOS.20,21 Another class of anti-hyperglycemic drugs, the sodium glucose cotransporter 2 (SGLT-2) inhibitors, which improve glycemic controls by increasing glucose excretion, are being evaluated in phase 2 (empagliflozin) and phase 3 (dapagliflozin) clinical trials in women with PCOS.22,23
Women with PCOS are at greater risk for ASCVD and having PCOS is considered a risk factor for atherosclerosis.24 Studies have shown that women with PCOS have a greater prevalence of dyslipidemia compared to BMI- and age-matched controls; with increased levels of low-density lipoprotein (LDL), very-low density lipoprotein (VLDL), and triglycerides (TG), as well as decreased levels of high-density lipoprotein (HDL).25 Managing CV risk in PCOS patients is recognized in the practice guidelines and recommendations. Statin therapy is a well-recognized treatment option which improves hypercholesterolemia and decreases CV risk by lowering LDL-C levels. 25 Recent studies have shown that statins can lower LDL-C in women with PCOS and support their use for controlling ASCVD risk in this patient population.25 At this point there is very little evidence for the use of newer agents (such as PCSK9 inhibitors) or other lipid-lowering treatments (such as omega-3 fatty acids) for CV risk reduction in this setting.
As the medical community continues to debate a name change for the condition, it is clear that the metabolic phenotype is an important component of PCOS, and experts have suggested a tight link between the metabolic and reproductive features. The high prevalence of cardiometabolic abnormalities puts women with PCOS at risk for developing insulin resistance, obesity, type 2 diabetes, and cardiovascular disease. Proper identification and screening approaches are crucial to identifying women with PCOS who are at an increased risk for metabolic imbalances. Awareness about strategies to decrease the cardiometabolic impacts of PCOS are needed, and clinicians treating PCOS should consider comprehensive and evidence-based approaches to reduce cardiometabolic risk.