Impact of insulin sensitising interventions on women with polycystic ovary syndrome and healthy humans

Polycystic ovary syndrome (PCOS) is the most common endocrinology condition in premenopausal women, with a prevalence of 8%-12% in this population. The presentation can vary between individuals, and although obesity is not part of the current diagnostic criteria, rates of obesity can range between 50%-80% in this patient population. PCOS is a common cause of anovulatory infertility, which an increased body mass index can compound. Lifestyle interventions with or without pharmacotherapy remain the mainstay of treatment, with bariatric surgery currently considered an experimental treatment. The first part of this thesis will address the impact of insulin sensitiser pharmacotherapy on metabolic and reproductive outcomes in women with PCOS who have overweight and obesity through a comprehensive systematic review, meta-analysis and meta- regression. Following this, the BAMBINI randomised controlled clinical trial will compare the effectiveness of medical care to bariatric surgery in improving the number of ovulatory cycles over 52 weeks in women with PCOS who have obesity. The use of an insulin sensitiser in women with PCOS who have overweight, or obesity resulted in a significant improvement in metabolic outcomes and some reproductive hormones; however, there was a lack of data for hard reproductive outcomes. Bariatric surgery proved superior to medical care in improving anthropometric, metabolic, and reproductive outcomes in women with PCOS who have obesity. Further randomised controlled trials are needed to investigate this effect and its impact on pregnancy outcomes. The second part will focus on the melanocortin system and its role in glucose homeostasis through melanocortin receptor agonism. Animal studies have shown that α-melanocyte stimulating hormone (α-MSH) – a melanocortin receptor agonist, increases skeletal muscle glucose uptake following a glucose load. In this first-in-human, double-blind, randomised, cross-over experimental study, healthy volunteers received α- MSH (initially at three different doses) and saline during an oral glucose tolerance test and subsequent euglycaemic hyperinsulinaemic clamp. The oral glucose tolerance tests were repeated in a different group of healthy volunteers with high dose α-MSH and saline. Infusion with α-MSH significantly reduced mean plasma glucose and serum insulin concentrations compared to saline.Open Acces

Bariatric Surgery in Women with Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine condition in premenopausal women and is a common cause of anovulatory subfertility. Although obesity does not form part of the diagnostic criteria, it affects a significant proportion of women with PCOS and is strongly implicated in the pathophysiology of the disease. Both PCOS and obesity are known to impact fertility in women; obesity also reduces the success of assisted reproductive technology (ART). With or without pharmacotherapy, lifestyle intervention remains the first-line treatment in women with PCOS and obesity. Bariatric surgery is still an experimental treatment in women with PCOS and subfertility. This review will present an overview of the pathophysiology of PCOS and obesity and the role of bariatric surgery. Although data are sparse regarding the impact of bariatric surgery on subfertility in women with PCOS and obesity, existing studies point to a beneficial role in treating metabolic and reproductive dysfunction. [Abstract copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Impact of insulin sensitisation on metabolic and fertility outcomes in women with polycystic ovary syndrome and overweight or obesity - a systematic review, meta-analysis, and meta-regression

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. This systematic review, meta-analysis and meta-regression aims to compare the effect of insulin sensitiser pharmacotherapy on metabolic and reproductive outcomes in women with PCOS and overweight or obesity. We searched online databases MEDLINE via OVID, EMBASE, Clinicaltrials.gov and EudraCT for trials published from inception to 13th November 2023. Inclusion criteria were double-blind, randomised controlled trials in women diagnosed with PCOS, body mass index (BMI) ≥ 25 kg/m2, which reported metabolic or reproductive outcomes. The intervention was insulin sensitisation pharmacotherapy versus placebo or other agents. The primary outcomes were the changes from baseline BMI, fasting blood glucose and menstrual frequency. Nineteen studies were included in this review. Metformin had the most significant effect on the fasting plasma glucose and body mass index. Insulin sensitiser pharmacotherapy significantly reduced fasting plasma glucose, body mass index, fasting serum insulin, HOMA-IR, sex hormone binding globulin and total testosterone, but the effect size was small. There was a lack of menstrual frequency and live birth data. The results indicate a role for insulin sensitisers in improving the metabolic and, to a lesser degree, reproductive profile in these women. Further research should examine insulin sensitisers' effects on objective measures of fecundity

Impact of insulin sensitization on metabolic and fertility outcomes in women with polycystic ovary syndrome and overweight or obesity—A systematic review, meta‐analysis, and meta‐regression

Summary: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive‐age women. This systematic review, meta‐analysis, and meta‐regression aims to compare the effect of insulin sensitizer pharmacotherapy on metabolic and reproductive outcomes in women with PCOS and overweight or obesity. We searched online databases MEDLINE via OVID, EMBASE, Clinicaltrials.gov, and EudraCT for trials published from inception to November 13, 2023. Inclusion criteria were double‐blind, randomized controlled trials in women diagnosed with PCOS, body mass index (BMI) ≥ 25 kg/m2, which reported metabolic or reproductive outcomes. The intervention was insulin sensitization pharmacotherapy versus placebo or other agents. The primary outcomes were changes from baseline BMI, fasting blood glucose, and menstrual frequency. Nineteen studies were included in this review. Metformin had the most significant effect on the fasting plasma glucose and body mass index. Insulin sensitizer pharmacotherapy significantly reduced fasting plasma glucose, body mass index, fasting serum insulin, HOMA‐IR, sex hormone binding globulin, and total testosterone, but the effect size was small. There was a lack of menstrual frequency and live birth data. The results indicate a role for insulin sensitizers in improving the metabolic and, to a lesser degree, reproductive profile in these women. Further research should examine insulin sensitizers' effects on objective measures of fecundity

Bariatric surgery for spontaneous ovulation in women living with polycystic ovary syndrome: the BAMBINI multicentre, open-label, randomised controlled trial

BackgroundPolycystic ovary syndrome (PCOS) is the most common cause of an ovulatory infertility. Obesity exacerbates the reproductive complications of PCOS; however, the management of obesity in women with PCOS remains a large unmet clinical need. Observational studies have indicated that bariatric surgery could improve the rates of ovulatory cycles and prospects of fertility; however, the efficacy of surgery on ovulation rates has not yet been compared with behavioural modifications and medical therapy in a randomised trial. The aim of this study was to compare the safety and efficacy of bariatric surgery versus medical care on ovulation rates in women with PCOS, obesity, and oligomenorrhoea or amenorrhoea.MethodsIn this multicentre, open-label, randomised controlled trial, 80 women older than 18 years, with a diagnosis of PCOS based on the 2018 international evidence-based guidelines for assessing and managing PCOS, and a BMI of 35 kg/m2 or higher, were recruited from two specialist obesity management centres and via social media. Participants were randomly assigned at a 1:1 ratio to either vertical sleeve gastrectomy or behavioural interventions and medical therapy using a computer-generated random sequence (PLAN procedure in SAS) by an independent researcher not involved with any other aspect of theclinical trial. The median age of the entire cohort was 31 years and 79% ofparticipants were White. The primary outcome was the number of biochemicallyconfirmed ovulatory events over 52 weeks, and was assessed using weekly serumprogesterone measurements. The primary endpoint included the intention-to-treatpopulation and safety analyses were per-protocol population. This study isregistered with the ISRCTN registry (ISRCTN16668711).FindingsParticipants were recruited from Feb 20, 2020 to Feb 1, 2021.40 participants were assigned to each group and there were seven dropouts in the medical group and ten dropouts in the surgical group. The median number of ovulations was 6 (IQR 3·5–10·0) in the surgical group and 2 (0·0–4·0) in the medical group. Women in the surgical group had 2.5 times more spontaneous ovulations compared with the medical group (incidence rate ratio 2·5 [95% CI1·5–4·2], p&lt;0·0007). There were more complications in the surgical group than the medical group, although without long-term sequelae. There were 24(66·7%) adverse events in the surgical group and 12 (30·0%) in the medical group. There were no treatment-related deaths.InterpretationBariatric surgery was more effective than medical care for the induction of spontaneous ovulation in women with PCOS, obesity, and oligomenorrhoea or amenorrhoea. Bariatric surgery could, therefore, enhance the prospects of spontaneous fertility in this group of women.</p