Cheryce L. Harrison

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.

Exercise therapy in polycystic ovary syndrome: a systematic review

BACKGROUND Polycystic ovary syndrome (PCOS) is a common endocrine disorder, affecting 8-12% of women. Lifestyle modification, including increased physical activity, is the first-line approach in managing PCOS. A systematic review was performed to identify and describe the effect of exercise as an independent intervention on clinical outcomes in PCOS. METHODS Five databases were searched with no time limit. A pre-specified definition of PCOS was not used. Studies were included if exercise therapy (aerobic and/or resistance) could be evaluated as an independent treatment against a comparison group. Outcomes measured included cardiovascular risk factors [insulin resistance (IR), lipid profiles, blood pressure and weight] and reproductive measures (ovulation, menstrual regularity and fertility outcomes). Quality analysis was performed based on the Cochrane Handbook of Systematic Reviews and the Quality of Reporting of Meta-Analyses checklist. RESULTS Eight manuscripts were identified (five randomized controlled trials and three cohort studies). All studies involved moderate intensity physical activity and most were of either 12 or 24 weeks duration with frequency and duration of exercise sessions ranging between studies. The most consistent improvements included improved ovulation, reduced IR (9-30%) and weight loss (4.5-10%). Improvements were not dependant on the type of exercise, frequency or length of exercise sessions. CONCLUSIONS Exercise-specific interventions in PCOS are limited. Studies vary considerably in design, intensity and outcome measures; therefore conclusive results remain elusive. Larger, optimally designed studies are needed to both gain insights into the mechanisms of exercise action and to evaluate the public health impact of exercise of PCOS.

Risk factors for gestational diabetes mellitus: Implications for the application of screening guidelines

Background:  Recent evidence has shown the importance of ensuring that all pregnancies with gestational diabetes mellitus (GDM) are identified and managed appropriately. However, there remains a lack of consensus as to how to best identify these women.

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.

Optimizing healthy gestational weight gain in women at high risk of gestational diabetes: a randomized controlled trial.

Optimizing gestational weight gain (GWG) in early pregnancy is of clinical and public health importance, especially in higher risk pregnancies.

Gestational diabetes: Development of an early risk prediction tool to facilitate opportunities for prevention

Background and aim: In the setting of advancing maternal age, escalating obesity and increasing Gestational Diabetes Mellitus (GDM) rates, we aimed to develop a novel risk prediction tool to identify high‐risk women in early pregnancy, specifically to facilitate targeted antenatal prevention of GDM.

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.

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.

Effects of antenatal diet and physical activity on maternal and fetal outcomes: Individual patient data meta-analysis and health economic evaluation

BACKGROUND Diet- and physical activity-based interventions in pregnancy have the potential to alter maternal and child outcomes. OBJECTIVES To assess whether or not the effects of diet and lifestyle interventions vary in subgroups of women, based on maternal body mass index (BMI), age, parity, Caucasian ethnicity and underlying medical condition(s), by undertaking an individual patient data (IPD) meta-analysis. We also evaluated the association of gestational weight gain (GWG) with adverse pregnancy outcomes and assessed the cost-effectiveness of the interventions. DATA SOURCES MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects and Health Technology Assessment database were searched from October 2013 to March 2015 (to update a previous search). REVIEW METHODS Researchers from the International Weight Management in Pregnancy Collaborative Network shared the primary data. For each intervention type and outcome, we performed a two-step IPD random-effects meta-analysis, for all women (except underweight) combined and for each subgroup of interest, to obtain summary estimates of effects and 95% confidence intervals (CIs), and synthesised the differences in effects between subgroups. In the first stage, we fitted a linear regression adjusted for baseline (for continuous outcomes) or a logistic regression model (for binary outcomes) in each study separately; estimates were combined across studies using random-effects meta-analysis models. We quantified the relationship between weight gain and complications, and undertook a decision-analytic model-based economic evaluation to assess the cost-effectiveness of the interventions. RESULTS Diet and lifestyle interventions reduced GWG by an average of 0.70 kg (95% CI -0.92 to -0.48 kg; 33 studies, 9320 women). The effects on composite maternal outcome [summary odds ratio (OR) 0.90, 95% CI 0.79 to 1.03; 24 studies, 8852 women] and composite fetal/neonatal outcome (summary OR 0.94, 95% CI 0.83 to 1.08; 18 studies, 7981 women) were not significant. The effect did not vary with baseline BMI, age, ethnicity, parity or underlying medical conditions for GWG, and composite maternal and fetal outcomes. Lifestyle interventions reduce Caesarean sections (OR 0.91, 95% CI 0.83 to 0.99), but not other individual maternal outcomes such as gestational diabetes mellitus (OR 0.89, 95% CI 0.72 to 1.10), pre-eclampsia or pregnancy-induced hypertension (OR 0.95, 95% CI 0.78 to 1.16) and preterm birth (OR 0.94, 95% CI 0.78 to 1.13). There was no significant effect on fetal outcomes. The interventions were not cost-effective. GWG, including adherence to the Institute of Medicine-recommended targets, was not associated with a reduction in complications. Predictors of GWG were maternal age (summary estimate -0.10 kg, 95% CI -0.14 to -0.06 kg) and multiparity (summary estimate -0.73 kg, 95% CI -1.24 to -0.23 kg). LIMITATIONS The findings were limited by the lack of standardisation in the components of intervention, residual heterogeneity in effects across studies for most analyses and the unavailability of IPD in some studies. CONCLUSION Diet and lifestyle interventions in pregnancy are clinically effective in reducing GWG irrespective of risk factors, with no effects on composite maternal and fetal outcomes. FUTURE WORK The differential effects of lifestyle interventions on individual pregnancy outcomes need evaluation. STUDY REGISTRATION This study is registered as PROSPERO CRD42013003804. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Understanding health behaviours in a cohort of pregnant women at risk of gestational diabetes mellitus: an observational study

Please cite this paper as: Harrison C, Lombard C, Teede H. Understanding health behaviours in a cohort of pregnant women at risk of gestational diabetes mellitus: an observational study. BJOG 2012;119:731–738.