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Background: Polycystic ovary syndrome (PCOS) and metabolic inflexibility are linked to insulin resistance, and women with PCOS appear to be metabolic inflexible in the rested, insulin-stimulated state. Exercise training is a primary lifestyle intervention in PCOS. Exercise training improves whole-body fat oxidation during submaximal exercise in healthy women, yet little is known about the effect on this outcome in women with PCOS.Methods: We measured whole-body fat oxidation rates during sub maximal exercise before and after 16 weeks of high-intensity interval training (HIT) in women with PCOS randomly allocated to either: low- or high-volume HIT (n = 41; low-volume HIT, 10 × 1 min work bouts at maximal, sustainable intensity and high-volume HIT, 4 × 4 min work bouts at 90–95% of maximal heart rate) or non-exercise control (n = 23), and in women without PCOS (Non-PCOS) allocated to low- or high volume HIT (n = 15). HIT was undertaken three times weekly. In a subset of women with and without PCOS, we measured mitochondrial respiration in abdominal and gluteal subcutaneous adipose tissue using high-resolution respirometry, as well as fat cell sizes in these tissues.Results: At baseline, women with PCOS had lower whole-body fat oxidation and mitochondrial respiration rates in abdominal adipose tissue compared to Non-PCOS. Peak oxygen uptake (mL/min/kg) increased in women with PCOS (~4%, p = 0.006) and Non-PCOS (~6%, p = 0.003) after 16 weeks of HIT. Whole-body fat oxidation only improved in Non-PCOS after HIT. No changes were observed in mitochondrial respiration and cell size in abdominal and gluteal adipose tissue after HIT in either group of women.Conclusion: We observed exercise-induced improvements in whole-body fat oxidation during submaximal exercise in Non-PCOS, but not in women with PCOS, after 16 weeks of HIT, suggesting metabolic inflexibility in women with PCOS.Clinical Trial Registration:www.clinicaltrials.gov, identifier NCT02419482 and NCT02943291.

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally. In women with polycystic ovary syndrome (PCOS), several miRNAs are differentially expressed compared to women without PCOS, suggesting a role for miRNAs in PCOS pathophysiology. Exercise training modulates miRNA abundance and is primary lifestyle intervention for women with PCOS. Accordingly, we measured the expression of eight circulating miRNAs selected a priori along with miRNA expression from gluteal and abdominal adipose tissue (AT) in 12 women with PCOS and 12 women matched for age and body mass index without PCOS. We also determined the miRNA expression “signatures” before and after high-intensity interval training (HIT) in 42 women with PCOS randomized to either: (1) low-volume HIT (LV-HIT, 10 × 1 min work bouts at maximal, sustainable intensity, n = 13); (2) high-volume HIT (HV-HIT, 4 × 4 min work bouts reaching 90–95% of maximal heart rate, n = 14); or (3) non-exercise control (Non-Ex, n = 15). Both HIT groups trained three times/week for 16 weeks. miRNAs were extracted from plasma, gluteal and abdominal AT, and quantified via a customized plate array containing eight miRNAs associated with PCOS and/or exercise training responses. Basal expression of circulating miRNA-27b (c-miR-27b), implicated in fatty acid metabolism, adipocyte differentiation and inflammation, was 1.8-fold higher in women with compared to without PCOS (P = 0.006) despite no difference in gluteal or abdominal AT miR-27b expression. Only the HV-HIT protocol increased peak oxygen uptake (VO2peak L/min; 9%, P = 0.008). There were no changes in body composition. In LV-HIT, but not HV-HIT, the expression of c-miR-27b decreased (0.5-fold, P = 0.007). None of the remaining seven circulating miRNAs changed in LV-HIT, nor was the expression of gluteal or abdominal AT miRNAs altered. Despite increased cardiorespiratory fitness, HV-HIT did not alter the expression of any circulating, gluteal or abdominal AT miRNAs. We conclude that women with PCOS have a higher basal expression of c-miR-27b compared to women without PCOS and that 16 weeks of LV-HIT reduces the expression of this miRNA in women with PCOS. Intense exercise training had little effect on the abundance of the selected miRNAs within subcutaneous AT depots in women with PCOS. Copyright © 2020 Lionett, Kiel, Camera, Vanky, Parr, Lydersen, Hawley and Moholdt. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Background: A physically active lifestyle is recommended to improve cardiometabolic health and fertility in women with polycystic ovary syndrome (PCOS), yet there are few randomized controlled trials investigating the effects of different exercise protocols on clinical reproductive outcomes. Our aim was to determine the effect of high-intensity interval training (HIT) on menstrual frequency, as a proxy of reproductive function, in women with PCOS. Methods: The IMPROV-IT study was a two-centre randomized controlled trial undertaken in Norway and Australia. Women with PCOS (Rotterdam criteria) were eligible for inclusion. After stratification for body mass index < or ≥27 kg/m2 and study centre, participants were randomly allocated by computer-generated random numbers (1:1:1) to high-volume HIT (HV-HIT), low-volume HIT (LV-HIT), or a control group. Measurements were assessed at baseline, after the 16-week exercise intervention and at 12-months follow-up. The primary outcome was menstrual frequency after 12 months. Secondary outcomes included markers of cardiometabolic and reproductive health, quality of life, and adherence to and enjoyment of HIT. Analysis was by intention-to-treat. Findings: The study took place between June 2015 and February 2020. We randomly allocated 64 participants to HV-HIT (n=20), LV-HIT (n=21), or the control group (n=23). There were no difference in menstrual frequency at 12 months between LV-HIT and control (frequency-ratio 0·09, 95%CI 0·06-0·12), HV-HIT and control (frequency-ratio 0·07, 95%CI 0·05-0·10) or LV-HIT and HV-HIT (frequency-ratio 0·09, 95%CI 0·07-0·13). More participants became pregnant in the LV-HIT group (n=5, 33·3%) than in the control group (n=0, p=0·02). Interpretation: HIT did not improve menstrual frequency in women with PCOS, but significantly increased pregnancy rate. Trial Registration: The study was registered in ClinicalTrials.gov (NCT02419482). Funding Statement: The Liaison Committee for Education, Research and Innovation in Central Norway, Norwegian University of Science and Technology, Australian Catholic University. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: Ethics approval was obtained from the Regional Committee for Medical and Health Research Ethics in Central Norway (REK-midt 2015/468) and the ACU Human Research Ethics Committee (2017-260H). The procedures for data entry, coding, and storage have been approved by the Regional Committee Medical Research Ethics in Central Norway. All participants were informed about the experimental protocol and potential risks verbally and in writing before providing their written informed consent.

IntroductionPolycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age and the leading cause of anovulatory infertility. Women with PCOS have a 15-fold higher prevalence of infertility, compared with women without PCOS, independent of body mass index (BMI). A healthy lifestyle is recommended to improve overall health and fertility in PCOS but there is limited evidence on the isolated effects of exercise, especially for reproductive outcomes. Previous findings indicate superior metabolic health benefits after vigorous compared with moderate-intensity exercise. Our primary aim is to determine the effect of high-intensity interval training (HIT) on menstrual frequency, as a proxy of reproductive function, in women with PCOS.Methods and analysisThe study is a two-centre, randomised, controlled trial with three parallel groups. Women (n=64) from Trondheim (Norway) and Melbourne (Australia) with PCOS according to the Rotterdam criteria will be randomly allocated (1:1:1) to high-volume HIT, low-volume HIT or a control group with no exercise after stratifying for BMI < or ≥ 27 kg/m2and study centre. Measurements for study end points will be undertaken at baseline, after a 16 week exercise intervention and at 12 months following baseline assessments. The primary outcome measure is menstruation frequency, measured as the number of self-reported menstrual bleedings divided by the number of expected menstrual bleedings during a 12-month period. Secondary outcome measurements include markers of cardiovascular, metabolic and reproductive health, as well as quality of life and adherence to and enjoyment of exercise.Ethics and disseminationThe Regional Committee Medical Research Ethics, Norway, and The Australian Catholic University Human Research Ethics Committee, Australia, have approved the trial protocol. This trial will provide new insight regarding the impact of exercise on fertility in PCOS. We expect this trial to contribute to new therapeutic exercise strategies as part of clinical care for women with PCOS.Trial registration numberClinical trial govNCT02419482.

Summary Objective Intensive lifestyle interventions (ILI) are criticised for ineffective obesity treatment because weight loss over time is modest and thus of limited clinical relevance. However, a subgroup (5–30%) maintains a clinical weight loss >10%, but it is not clear if cardiometabolic health follows this pattern. The aim was to study the effect of different magnitudes of weight loss maintenance after ILI on cardiometabolic health. Methods Eighty out of 2420 former participants (age: 36 ± 1, BMI: 38 ± 1, (means ±SE)) in an 11–12-week ILI were recruited into 3 groups; clinical weight loss maintenance (>10% weight loss), moderate maintenance (1–10%), and weight regain based on weight loss at follow-up (5.3 ± 0.4 years). Weight loss during the ILI was achieved by increased physical activity and hypo-caloric diet. Dual X-ray Absorptiometry, blood sample, skeletal muscle biopsy and VO 2max test were used to determine cardiometabolic health at follow-up. Results At follow-up, the clinical weight loss maintenance group scored better in the following variables compared to the other groups: BMI (31 ± 1, 33 ± 2, 43 ± 2 kg/m 2 ), composition (34 ± 2, 40 ± 1, 49 ± 1% fat), visceral adipose tissue (0.8 ± 0.2, 1.7 ± 0.5, 2.4 ± 0.4 kg), plasma triglycerides (0.8 ± 0.2, 1.3 ± 0.4, 1.6 ± 0.3 mmol/L), plasma glucose (4.9 ± 0.1, 5.9 ± 0.4, 5.9 ± 0.1 mmol/L), Hb1Ac (5.1 ± 0.0, 5.6 ± 0.2, 5.8 ± 0.2%), protein content in skeletal muscle of GLUT4 (1.5 ± 0.2, 0.9 ± 0.1, 1.0 ± 0.1 AU) and hexokinase II (1.6 ± 0.2, 1.0 ± 0.2, 0.7 ± 0.1 AU), citrate synthase activity (155 ± 6, 130 ± 5, 113 ± 5 μmol/g/min) and VO 2max (49 ± 1, 43 ± 1, 41 ± 1 mL/min/FFM) (p Conclusion Cardiometabolic health is better in participants who have maintained >10% weight loss compared to moderate weight loss and weight regain.