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Insulin resistance: and polycystic ovary syndrome (PCOS): Part 1. The impact of insulin resistance.

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females of reproductive age (1,2) with a prevalence of up to 20%. (3) It is a multifactorial complex reproductive, endocrine, metabolic and psychological condition with insulin resistance playing a major role in its pathogenesis. (2,4-11) Women with PCOS have a higher risk of cardiometabolic conditions. (12) Insulin resistance has been implicated in numerous health conditions, such as cardiometabolic syndrome (13,14) and PCOS. (13)

This paper aims to briefly describe PCOS, insulin resistance and its impact on PCOS. It is not an exhaustive review but rather aims to shed light on these complex conditions. Part 2 will discuss the potential impact of diet, nutrients, and herbal medicine on insulin resistance in PCOS.

Polycystic Ovary Syndrome (PCOS)

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in females of reproductive age (1,2,11,15) with a prevalence of up to 20%. (3) In Australia, the prevalence is approximately 12-21% of reproductive-age women. (16) Furthermore, an Australian study found the prevalence of PCOS was 12% in a cohort of young females aged 16-29 years. (17) Approximately 70% of Australian women with PCOS remain undiagnosed. (16) PCOS is a complex condition with reproductive, endocrine, metabolic and psychological features. (18) As long ago as 1935, Stein and Leventhal described the association of oligomenorrhoea or amenorrhoea, hirsutism, and obesity with polycystic ovaries. (19) PCOS is characterised by polycystic ovaries, anovulation, amenorrhoea, hyperandrogenaemia, hirsutism, acne, and infertility. (4,16) It must be noted that ovulatory dysfunction can still occur with regular menstrual cycles. (18) PCOS is not only a reproductive condition but is also a lifelong metabolic disorder. (15)

For the diagnosis of PCOS, ultrasound can be used to check for polycystic ovaries and endometrial thickness. Blood tests include androgen levels, thyroid function tests, prolactin and follicle-stimulating hormone levels, glycaemic status (fasting glucose and oral glucose tolerance test) and lipid profile. (18) Family history should also be investigated. (18) The use of ultrasound as a diagnostic tool in adolescents remains controversial. This is due to the polycystic appearance of the ovaries being very common. This potentially leads to overdiagnosis or misdiagnosis. (18) There is no single specific diagnostic test for PCOS. (19) Some of the common reactions to a diagnosis of PCOS have been noted as "unhappy", "worried", "scared", and/or "confused". (17) Studies have found that there is an increased fear of infertility and of not having children in those diagnosed with PCOS. Additionally, only a small percentage of those diagnosed had an understanding of their diagnosis of PCOS. (17)

Women with PCOS have an increased risk of cardiometabolic syndrome, (12) insulin resistance, (2,411,19) impaired glucose tolerance, (4) type 2 diabetes, (16,18) dyslipidaemia (altered cholesterol and triglycerides), (4,19) inflammation, (4,8,19,20) oxidative stress, (4) impaired endothelial dysfunction, (2,4,5) depression, anxiety, (16,18) low self-esteem, (16) negative psychosocial impact, body image issues, disordered eating, gestational diabetes, and obstructive sleep apnoea. (18) PCOS represents one of the most frequent causes of secondary amenorrhea and infertility, due to chronic anovulation and hyperandrogenism. (21) All of these negatively affect quality of life. (11,16,18) Changes in the menstrual cycle, or irregular or absent menstrual periods can all result in psychological and emotional distress. This distress can be amplified when there is difficulty conceiving. A combination of these conditons can influence the feminine identity of females with PCOS. Perceptions of physical appearance when compared to society's "ideal" appearance can have negative impact on emotional wellbeing and negatively affect women's quality of life. (22) PCOS is a very frustrating experience for women. (16)

The pathogenesis of PCOS includes insulin resistance and low-grade inflammation, and women with PCOS have an increased risk of metabolic syndrome. Insulin resistance and low-grade inflammation in PCOS can be associated with increased risk of development of cardiovascular disease. (8) One of the earliest reports linking insulin resistance to PCOS was in 1921. (19) Metabolic syndrome occurs in up to one-third of adolescents with PCOS and nearly half of female adults with PCOS. (23)

Previously it was thought that PCOS occurred predominantly in overweight or obese women. (21) However, research indicates that approximately half of all women with PCOS are overweight or obese, (24) meaning that half are underweight or are of "normal" weight range. Therefore, it is noted that women can present with PCOS at any BMI (19) and the authors of this paper contend that the weight of the person should not be the driving factor in the diagnosis of PCOS. Studies have reported that there are endocrine and metabolic differences between lean and overweight/obese women with PCOS. (24) One of these differences is higher postprandial insulin levels in underweight women with PCOS. (25) These findings suggest that further research is recommended to investigate these differences.

Insulin and Insulin Resistance

Research into the relationship and effects of the pancreas and type 2 diabetes escalated in the early 1900's, including prescribing extracts of the pancreas. (26) On 30 October 1920, Dr Frederick Banting was preparing a lecture on the relationship of the pancreas to diabetes. Afterwards, he read an article on the pancreatic duct in a medical journal and was unable to sleep. It got him thinking that there seemed to be an unclear relationship between the islet cells of the pancreas and diabetes. (27) This led him into researching further. Banting noted in 1926 that it was indisputably proven that adequate amounts of insulin are essential for normal metabolism of carbohydrates in the body. (26)

Insulin is a hormone produced by beta cells in the pancreas. Insulin has many functions, including the metabolism of glucose, reducing blood glucose levels by inducing glucose uptake in insulin-sensitive tissue (such as skeletal muscle, fat and heart), (28) and stimulation of a variety of synthesis pathways, for example, the synthesis of glycogen, protein, and lipids. (28,29) Insulin inhibits glucose production in the liver, kidney, and small intestine in the process in controlling blood glucose. (28) It also promotes mitochondrial function, improves microcirculation, and induces cell proliferation. (28) Insulin simultaneously down-regulates lipolysis. (29) Following the consumption of food, insulin promotes carbohydrate uptake at key storage sites and prompts the conversion of carbohydrate and protein to lipids. This conversion to lipids is a more efficient storage of energy. (30) Insulin provides an essential integrated set of signals that allow the body to balance nutrient availability with the body's demands. (30) The following is a brief review of the role of insulin in the fed and fasted state. In the fed state, dietary carbohydrate increases plasma glucose and promotes insulin secretion from the pancreatic [beta]-cells. In skeletal muscle, insulin increases glucose transport, permitting glucose entry, and the synthesis of glycogen. In the liver, insulin promotes the synthesis of glycogen and de novo lipogenesis while also inhibiting gluconeogenesis. In adipose tissue, insulin suppresses lipolysis and promotes lipogenesis. (30) In the fasted state, the secretion of insulin is decreased. This decreased level of insulin serves to increase hepatic gluconeogenesis and promote glycogenolysis, thereby providing more glucose as a fuel. The production of lipids in the liver decreases while adipose lipolysis increases. (30)

Insulin resistance has been recognised as one of the earliest predictors and causative factors of metabolic disease. (29) The concept of insulin resistance underlying metabolic syndrome was proposed by Reaven in 1988. (31) Insulin resistance can be defined as the inability of insulin to optimally stimulate the transport of glucose into the body's cell. (28,32) It is a state that requires more insulin to obtain the biological effects achieved by a lower amount of insulin in a normal state. (33) Resistance to insulin-stimulated glucose uptake can be present in the majority of people with impaired glucose tolerance or type 2 diabetes and in approximately 25% of non-obese individuals with normal oral glucose tolerance. (31) Insulin resistance is a key feature of metabolic syndrome, type 2 diabetes, coronary artery disease, and hypertension. (33) Under conditions of chronic nutrient overload (such as a high fat diet), peripheral tissues experience a decrease in sensitivity to insulin. This leads to additional insulin being required in both the fed and fasted states. This is to restore and maintain normal blood glucose concentration. Impaired glucose metabolism, (29) defects within the insulin signalling pathways (29,33) and insulin receptors, (29) reduced capillary permeability to insulin, (34) and defects in insulin action in adipocytes amplify insulin resistance. (29) The characteristics of insulin resistance include fasting hyperinsulinaemia and hyperglycaemia, postprandial hyperglycaemia, impaired glucose tolerance, impaired insulin tolerance, decreased glucose infusion rate, increased hepatic glucose production, loss of first phase secretion of insulin, increased glycosylated haemoglobin, hyperlipidaemia, and hypoadiponectinaemia. (28) Insulin resistance is a complex multifactorial metabolic disorder that has no single cause (30) Some of the numerous causes include ageing, endoplasmic reticulum stress, (28,35) fatty liver disease, (28,36) genetic background, hyperinsulinaemia, (28,37) reduced capillary permeability to insulin, (34) hyperlipidaemia, (28) hypoxia, (28,38) inflammation, (20,28,35,37,39,40) lipotoxicity, (28) mitochondria] dysfunction, (28,35) obesity, (28,39) and oxidative stress, (28,35,37) (see Table 1).

Hyperglycaemia is a well-established risk factor for cardiovascular disease, with research showing that impaired fasting glucose and impaired glucose tolerance are associated with increases in the risk for cardiovascular disease. (41) People who are insulin resistant have a tendency to lose the vasodilatory effect of insulin. This loss of effect leads to elevated blood pressure. (42) It should be noted that excess abdominal fat is associated with insulin resistance. As a combination, excess abdominal fat and insulin resistance lead to an increase in the production of reactive oxygen species and inflammation, in turn leading to increased insulin resistance. (42) This is a cyclic effect. Inflammation amplifies insulin resistance. (30) Similarly to PCOS, a significant degree of insulin resistance exists in non-obese patients with PCOS. (43)

Cardiometabolic Syndrome

Cardiovascular disease is the leading cause of morbidity and death worldwide. (13) Metabolic syndrome is a multifactorial risk factor for cardiovascular disease and type 2 diabetes. (13) Cardiometabolic syndrome comprises the clustering of several cardiometabolic risk factors related to insulin resistance and abdominal obesity, (13,14) with insulin resistance being one of the main drivers of cardiometabolic syndrome. (42) Metabolic syndrome is diagnosed when any three of the following five risk factors are present: elevated triglyceride levels, elevated fasting plasma glucose level (hyperglycaemia), elevated blood pressure, increased waist circumference, and reduced high-density lipoprotein (HDL) cholesterol level. (13) Additionally, chronic inflammation, (13,44) oxidative stress, (14,44) endothelial dysfunction, (14) hypercoagulability, (14) and prothrombotic state (13) have been associated with cardiometabolic syndrome. Cardiovascular risk is increased due to the interaction of these multiple risk factors. (45) It should be noted that people of all ages can be affected by the components of cardiometabolic syndrome. (13)

There are numerous health consequences related to cardiometabolic syndrome, including PCOS, non-reproductive dysfunction, (13) coronary heart disease, myocardial infarction, stroke, (42) significantly increased risk of total mortality and cardiovascular morbidity, (46) obesity, overweight, high adiposity, alcoholic fatty liver disease, and obstructive sleep apnoea. (13) Cardiometabolic syndrome is generally regarded as a proinflammatory state. (13) Inflammation drives insulin resistance and oxidative stress, (47) further amplifying the condition (see Figure 1).

PCOS and Insulin Resistance

Insulin resistance is a common feature in PCOS. (6,7) In PCOS, there are defects in the insulin-stimulated glucose uptake, glycogen synthesis, and in the oxidation of glucose and lipids. (10) PCOS is a state in which resistance to the glucose-metabolic effects of insulin seems to be paradoxically associated with ovarian sensitivity to insulin. This compensatory hyperinsulinaemia of insulin resistance contributes to ovarian androgen excess. (23) Insulin resistance in PCOS is characterised by reduced sensitivity and responsiveness to insulin-mediated glucose utilisation primarily in skeletal muscle and adipose tissue. (23) Insulin resistance in PCOS can be observed in both lean and overweight/obese women with PCOS. (19) Research has found that young women with PCOS have a similar degree of insulin resistance to that seen in middle-aged patients with type 2 diabetes. (10)

Androgen excess is a defining feature of PCOS. (15)

Hyperinsulinaemia stimulates ovarian androgen production and contributes to hyperandrogenaemia. (19) Hyperandrogenic states can be up-regulated by mechanisms that involve insulin resistance. (23) Insulin stimulates testosterone formation in fat (23) and ovarian testosterone production by theca cells. (19) Sex hormone-binding globulin levels are raised by oestrogen and suppressed by androgen, insulin resistance in obesity, and hypothyroidism. (23) Calculated free testosterone, free androgen index or calculated bioavailable testosterone can be used to assess biochemical hyperandrogenism in the diagnosis of PCOS. (18) Sex hormone-binding globulin is an important factor in androgen action and metabolism. The sex hormone-binding globulin concentration determines the fraction of serum testosterone and other (17) [beta]-hydroxysteroid ligands (for example, oestradiol, dihydrotestosterone) that are free or bound to albumin. (23)

A comprehensive history and physical examination should always be completed for signs and symptoms of clinical hyperandrogenism. The signs of clinical hyperandrogenism include acne, alopecia, and hirsutism. In adolescents, these include severe acne and hirsutism. (18) In patients with irregular menstrual cycles and hyperandrogenism, an ultrasound of the ovaries is not necessary for PCOS diagnosis. However, ultrasound can be used to identify the extent of polycystic ovaries. (18) Although useful, serum Anti-Mullerian hormone levels should not yet be used as an alternative for the detection of polycystic ovarian morphology or as a single test for the diagnosis of PCOS. (18) Further research is suggested here.

Insulin resistance and cardiometabolic syndrome are diseases of unhealthy diet and lifestyle. Diet, nutrition, and herbal medicine play major roles in the prevention and management of chronic disease, especially cardiometabolic syndrome. (48,49) Women have highlighted delayed diagnosis and dissatisfaction with care. (18) Part 2 will discuss the potential of diet, nutrients, and herbal medicine in the management of insulin resistance in PCOS.

Conclusion

Polycystic ovary syndrome is the most common endocrine disorder in females of reproductive age with a prevalence of up to 20%. It is estimated that 70% of Australian women with PCOS remain undiagnosed. Insulin resistance results in numerous cardiometabolic effects. Women with PCOS have a higher risk of cardiometabolic syndrome and insulin resistance, among other physical, emotional, and mental health conditions. PCOS can present at any BMI. Part 2 will discuss the potential impact of diet, nutrients, and herbal medicine on insulin resistance in PCOS.

We, the authors of this paper (McEwen and Hartmann), wish to strongly state that PCOS (19) and insulin resistance (23) occur in women of all sizes and that weight should not be the determining factor or the only focus in the diagnosis and treatment of PCOS. This is inappropriate as this may put undue stress on a person who is already at risk of self-consciousness about appearance, (22,50) lower body satisfaction, tendencies towards social avoidance, and depression. (50)

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Bradley McEwen | PhD, MHSc (Hum Nutr), BHSc, ND (Adv), DBM, DNutr, DSM, M.ATMS, Naturopath, Nutritionist, and Mentor

Georgia Hartmann | BHSc (Naturopathy) Naturopath, Nutritionist
Table 1. Some of the causes of insulin resistance

Ageing                          Hypoxia
Endoplasmic reticulum stress    Inflammation
Fatty liver disease             Lipotoxicity
Genetic background              Mitochondrial dysfunction
Hyperinsu linaemia              Obesity
Hyperlipidaemia                 Oxidative stress
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Author:Mcewen, Bradley; Hartmann, Georgia
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Date:Jun 22, 2018
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