Samantha K. Hutchison

Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic–hyperinsulaemic clamp

STUDY QUESTION What is the prevalence of insulin resistance (IR) and the contributions of intrinsic and extrinsic IR in women diagnosed with polycystic ovary syndrome (PCOS) according to the Rotterdam criteria? SUMMARY ANSWER We report novel clamp data in Rotterdam diagnosed PCOS women, using World Health Organization criteria for IR showing that women with PCOS have a high prevalence of IR, strengthening the evidence for an aetiological role of IR in both National Institutes of Health (NIH) and Rotterdam diagnosed PCOS in lean and overweight women. WHAT IS KNOWN ALREADY PCOS is a complex endocrine condition with a significant increased risk of gestational diabetes and type 2 diabetes. STUDY DESIGN, SIZE, DURATION Using a cross-sectional study design, 20 overweight and 20 lean PCOS (Rotterdam criteria), 14 overweight and 19 lean body mass index (BMI)-matched control non-PCOS women underwent clinical measures of IR after a 3-month withdrawal of insulin sensitizers and the oral contraceptive pill. MATERIALS, SETTING, METHODS In an academic clinic setting, glucose infusion rate (GIR) on euglycaemic-hyperinsulinaemic clamp was investigated as a marker of insulin sensitivity. MAIN RESULTS AND THE ROLE OF CHANCE PCOS women were more IR than BMI-matched controls (main effect for BMI and PCOS; P < 0.001). IR was present in 75% of lean PCOS, 62% of overweight controls and 95% of overweight PCOS. Lean controls (mean ± SD; GIR 339 ± 76 mg min⁻¹ m⁻²) were less IR than lean PCOS (270 ± 66 mg min⁻¹ m⁻²), overweight controls (264 ± 66 mg min⁻¹ m⁻²) and overweight PCOS (175 ± 96 mg min⁻¹ m⁻²). The negative relationship between BMI and IR reflected by GIR was more marked in PCOS (y = 445.1 - 7.7x, R² = 0.42 (P < 0.0001) than controls (y = 435.5 - 4.6x, R² = 0.04 (P < 0.01)). LIMITATIONS, REASONS FOR CAUTION The study did not use glucose tracer techniques to completely characterize the IR, as well as the lack of matching for body composition and age. WIDER IMPLICATIONS OF THE FINDINGS IR is exacerbated by increased BMI, supporting intrinsic IR in PCOS. BMI impact on IR is greater in PCOS, than in controls, irrespective of visceral fat, prioritizing lifestyle intervention and the need for effective therapeutic interventions to address intrinsic IR and prevent diabetes in this high-risk population. STUDY FUNDING/COMPETING INTEREST(S) This investigator-initiated trial was supported by grants from the National Health & Medical Research Council (NHMRC) Grant number 606553 (H.J.T., N.K.S. and S.K.H.) as well as Monash University and The Jean Hailes Foundation. H.J.T. is an NHMRC Research Fellow. N.K.S. is supported through the Australian Governments Collaborative Research Networks (CRN) programme. A.E.J. is a Jean Hailes and NHMRC scholarship holder. The authors declare that there is no conflict of interest associated with this manuscript.

The management of insulin resistance in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) has reproductive and metabolic implications. Insulin resistance (IR), secondary to genetic and lifestyle factors, is integral in the pathogenesis, metabolic, clinical features and the long-term sequelae in the majority of people with PCOS. Therapeutic strategies targeting IR in PCOS ameliorate clinical features and might reduce long-term sequelae including diabetes. The mainstay for improving IR is lifestyle change; however, feasibility and sustainability remain concerns. In PCOS, metformin reduces IR, improves ovarian function, regulates cycles, lowers androgens, improves clinical hyperandrogenism and potentially improves fertility. Metformin is also likely to delay diabetes onset and has a role in PCOS in those at high risk of diabetes; however, further research is needed to clarify specific target subgroups and clinical indications.

Effects of exercise on insulin resistance and body composition in overweight and obese women with and without polycystic ovary syndrome

CONTEXT Polycystic ovary syndrome (PCOS) is an insulin-resistant (IR) state. Visceral fat (VF) is independently associated with IR. OBJECTIVES The objectives of the study were to explore mechanisms underpinning IR by assessing the effect of exercise training on IR and body composition in overweight PCOS and non-PCOS women. DESIGN This was a prospective exercise intervention study. SETTING AND PARTICIPANTS The study was conducted at an academic medical center. Participants included 20 overweight PCOS and 14 overweight non-PCOS women. INTERVENTION The intervention included 12 wk of intensified aerobic exercise (3 h/wk). MAIN OUTCOME MEASURES IR on euglycemic hyperinsulinemic clamp, body composition including abdominal visceral and sc fat distribution by computer tomography and lipids was measured. RESULTS PCOS subjects were more IR (P = 0.02) and had more VF (P = 0.04 age adjusted) than non-PCOS women. In PCOS women, IR correlated with VF (r = -0.78, P < 0.01). With exercise training, both groups maintained weight but within PCOS, VF (-12.0 cm(2), P = 0.03) and within non-PCOS abdominal sc fat (-40.2 cm(2), P = 0.02) decreased. Despite exercise-induced improvement in IR within PCOS (+27.9 mg · m(-2) · min(-1), P = 0.03), no relationship with decreased VF (r = -0.08, P = 0.84) and no differential changes in IR and VF between groups were noted. Triglycerides decreased within PCOS (-0.27 mmol/liter, P = 0.02) and decreased differentially between groups (P < 0.01). CONCLUSIONS Higher IR was related to increased VF in PCOS, suggesting an etiological role for VF in intrinsic IR in PCOS; however, changes with exercise intervention did not support a causal relationship. Triglycerides were modulated more by exercise training in PCOS than non-PCOS women. Within-group exercise-induced reductions in cardiometabolic risk factors including IR, triglycerides, and VF in PCOS were observed without significant weight loss and if confirmed in future controlled trials, suggest weight loss should not be the sole focus of exercise programs.

Insulin resistance, the metabolic syndrome, diabetes, and cardiovascular disease risk in women with PCOS

Polycystic ovary syndrome is the most common endocrinopathy of reproductive aged women affecting 6–10% of the population. Traditionally considered a reproductive disorder manifesting as chronic anovulation, infertility, and hyperandrogenism, management has primarily focused on short-term reproductive outcomes. Recently, however, significant metabolic aspects in conjunction with longer-term health sequalae of PCOS have been recognized. The metabolic features are primarily related to underlying insulin resistance (IR), which is now understood to play an important role in both the pathogenesis and long-term sequelae of PCOS.

The impact of intensified exercise training on insulin resistance and fitness in overweight and obese women with and without polycystic ovary syndrome

Objective  To evaluate mechanisms of insulin resistance (IR) in overweight and obese women with and without polycystic ovary syndrome (PCOS) and explore relationships between IR, fitness and body mass index (BMI) at baseline and following exercise intervention.

A comprehensive assessment of endothelial function in overweight women with and without polycystic ovary syndrome.

PCOS (polycystic ovary syndrome) is associated with reproductive abnormalities, IR (insulin resistance) and elevated risk factors for CVD (cardiovascular disease) and Type 2 diabetes, including endothelial dysfunction. The present study aimed to assess a range of circulating markers of endothelial function in overweight women with and without PCOS. Overweight and obese age- and BMI (body mass index)-matched women with (n=80) and without (n=27) PCOS were assessed in a cross-sectional study. End-point measures were HOMA (homoeostasis model assessment)-IR, androgens, lipids, inflammatory markers [hsCRP (high-sensitivity C-reactive protein)] and endothelial function [FMD (flow-mediated dilation), ADMA (asymmetric dimethylarginine), PAI-1 (plasminogen activator inhibitor-1) and vWF (von Willebrand factor)]. Women with PCOS had elevated HOMA-IR (4.1+/-3.4 compared with 1.9+/-1.4), free androgen index (9.3+/-5.6 compared with 4.6+/-3.8), total cholesterol (5.2+/-1.0 compared with 4.7+/-0.9 mmol/l) and triacylglycerols (triglycerides; 1.4+/-0.7 compared with 0.9+/-0.3 mmol/l) (P<0.05 for all), but similar hsCRP compared with women without PCOS. With regard to endothelial function, women with PCOS had elevated ADMA (1.0+/-0.4 compared 0.3+/-0.1 mumol/l, P<0.001) and PAI-1 (5.6+/-1.8 compared with 4.6+/-1.1 units/ml, P=0.006), a trend towards worsened FMD (11.8+/-5.0 compared with 13.5+/-4.0%, P=0.075) and no difference in vWF compared with controls. For all subjects, ADMA (P=0.002) and PAI-1 (P<0.001) were increased with higher tertiles of HOMA-IR. Women with PCOS are hyperandrogenic, dyslipidaemic and have IR, and have risk factors for CVD and diabetes including increased circulating markers of endothelial function (ADMA and PAI-1) and a trend towards worse FMD as a global marker of endothelial function. In PCOS, deterioration in endothelial function is related to IR, hyperandrogenism and other factors.

Endothelial function and insulin resistance in polycystic ovary syndrome: the effects of medical therapy

OBJECTIVE To assess the interaction between insulin resistance and endothelial function and the optimal treatment strategy addressing cardiovascular risk in polycystic ovary syndrome. DESIGN Randomized controlled trial. SETTING Controlled clinical study. PATIENT(S) Overweight age- and body mass index-matched women with polycystic ovary syndrome. INTERVENTION(S) Six months metformin (1 g two times per day, n = 36) or oral contraceptive pill (OCP) (35 microg ethinyl E(2)-2 mg cytoproterone acetate, n = 30). MAIN OUTCOME MEASURE(S) Fasting and oral glucose tolerance test glucose and insulin levels, endothelial function (flow-mediated dilation, asymmetric dimethylarginine, plasminogen activator inhibitor-1, von Willebrand factor), inflammatory markers (high-sensitivity C-reactive protein), lipids, and hyperandrogenism. RESULT(S) The OCP increased levels of glucose and insulin on oral glucose tolerance test, high-sensitivity C-reactive protein, triglycerides, and sex-hormone binding globulin and decreased levels of low-density lipoprotein cholesterol and T. Metformin decreased levels of fasting insulin, oral glucose tolerance test insulin, high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. Flow-mediated dilation increased only with metformin (+2.2% +/- 4.8%), whereas asymmetric dimethylarginine decreased equivalently for OCP and metformin (-0.3 +/- 0.1 vs. -0.1 +/- 0.1 mmol/L). Greater decreases in plasminogen activator inhibitor-1 occurred for the OCP than for metformin (-1.8 +/- 1.6 vs. -0.7 +/- 1.7 U/mL). CONCLUSION(S) In polycystic ovary syndrome, metformin improves insulin resistance, inflammatory markers, and endothelial function. The OCP worsens insulin resistance and glucose homeostasis, inflammatory markers, and triglycerides and has neutral or positive endothelial effects. The effect of the OCP on cardiovascular risk in polycystic ovary syndrome is unclear.

Retinol-Binding Protein 4 and Insulin Resistance in Polycystic Ovary Syndrome

OBJECTIVE—Polycystic ovary syndrome (PCOS) is an insulin-resistant state with insulin resistance being an established therapeutic target; however, measurement of insulin resistance remains challenging. We aimed to 1) determine serum retinol-binding protein 4 (RBP4) levels (purported to reflect insulin resistance) in women with PCOS and control subjects, 2) examine the relationship of RBP4 to conventional markers of insulin resistance, and 3) examine RBP4 changes with interventions modulating insulin resistance in overweight women with PCOS. RESEARCH DESIGN AND METHODS—At baseline, 38 overweight women (BMI >27 kg/m2) with PCOS and 17 weight-matched control subjects were compared. Women with PCOS were then randomly assigned to 6 months of a higher-dose oral contraceptive pill (OCP) (35 μg ethinyl estradiol/2 mg cyproterone acetate) or metformin (1 g b.i.d.). Outcome measures were insulin resistance (total insulin area under the curve) on an oral glucose tolerance test, RBP4, and metabolic/inflammatory markers. RESULTS—Overweight women with PCOS were more insulin resistant than control subjects, yet RBP4 levels were not different in women with PCOS versus those in control subjects (35.4 ± 4.3 vs. 28.9 ± 3.1 μg/ml, P = 0.36). RBP4 correlated with cholesterol and triglycerides but not with insulin resistance. Metformin improved insulin resistance by 35%, whereas the OCP worsened insulin resistance by 33%. However, RBP4 increased nonsignificantly in both groups (43.7 ± 6.3 vs. 42.6 ± 5.5 μg/ml, P = 0.92). CONCLUSIONS—Overweight women with PCOS were more insulin resistant than control subjects, but this finding was not reflected by RBP4 levels. RBP4 correlated with lipid levels but not with insulin resistance markers. RBP4 levels did not change when insulin resistance was reduced by metformin or increased by the OCP. These data suggest that RBP4 is not a useful marker of insulin resistance in PCOS but may reflect other metabolic features of this condition.

Exercise decreases anti-müllerian hormone in anovulatory overweight women with polycystic ovary syndrome: a pilot study.

Polycystic ovary syndrome (PCOS) is a common condition in women associated with menstrual irregularity and anovulation. While obesity worsens and weight loss or exercise improves reproduction function in PCOS, the mechanism for this is unclear. The aim of this study was to examine the effect of exercise on ovarian hormones [anti-Müllerian hormone (AMH)] and menstrual and ovulatory function in women with and without PCOS. Overweight women with (n=7) and without (n=8) PCOS of comparable age, weight and BMI undertook a 12-week intensified endurance exercise training program (1 h 3 times/week) with no structured energy restriction. Primary outcomes were AMH, ovulation (weekly urinary pregnanediol) and menstrual regularity. Secondary outcomes were insulin resistance (euglycemic hyperinsulinemic clamp) and body composition (computed tomography and dual X-ray absorptiometry). Exercise decreased BMI, total and android fat mass and improved insulin sensitivity for all women. AMH was significantly higher in women with PCOS compared to controls before (p<0.001) and after exercise (p=0.001). There was a significant interaction between AMH changes with exercise and PCOS status (p=0.007) such that women without PCOS had no change in AMH (+1.4±5.2 pmol/l, p=0.48) while women with PCOS had a decrease in AMH (- 13.2±11.7 pmol/l, p=0.025). Exercise is associated with improvements in ovarian hormones in women with abnormal ovarian function. This suggests that mechanisms associated with ovarian dysfunction can be improved by exercise in PCOS.

Pigment Epithelium‐Derived Factor, Insulin Sensitivity, and Adiposity in Polycystic Ovary Syndrome: Impact of Exercise Training

Pigment epithelium‐derived factor (PEDF) is upregulated in obese rodents and is involved in the development of insulin resistance (IR). We aim to explore the relationships between PEDF, adiposity, insulin sensitivity, and cardiovascular risk factors in obese women with polycystic ovary syndrome (PCOS) and weight‐matched controls and to examine the impact of endurance exercise training on PEDF. This prospective cohort intervention study was based at a tertiary medical center. Twenty obese PCOS women and 14 non‐PCOS weight‐matched women were studied at baseline. PEDF, cardiometabolic markers, detailed body composition, and euglycemic—hyperinsulinemic clamps were performed and measures were repeated in 10 PCOS and 8 non‐PCOS women following 12 weeks of intensified aerobic exercise. Mean glucose infusion rate (GIR) was 31.7% lower (P = 0.02) in PCOS compared to controls (175.6 ± 96.3 and 257.2 ± 64.3 mg.m−2.min−1) at baseline, yet both PEDF and BMI were similar between groups. PEDF negatively correlated to GIR (r = −0.41, P = 0.03) and high‐density lipoprotein (HDL) (r = −0.46, P = 0.01), and positively to cardiovascular risk factors, systolic (r = 0.41, P = 0.02) and diastolic blood pressure (r = 0.47, P = 0.01) and triglycerides (r = 0.49, P = 0.004). The correlation with GIR was not significant after adjusting for fat mass (P = 0.07). Exercise training maintained BMI and increased GIR in both groups; however, plasma PEDF was unchanged. In summary, PEDF is not elevated in PCOS, is not associated with IR when adjusted for fat mass, and is not reduced by endurance exercise training despite improved insulin sensitivity. PEDF was associated with cardiovascular risk factors, suggesting PEDF may be a marker of cardiovascular risk status.