Clinical Effects of Glucagon-Like Peptide-1 Agonist Use for Weight Loss in Women With Polycystic Ovary Syndrome: A Scoping Review

Glucagon-like peptide-1 (GLP-1) is a gastrointestinal regulatory hormone that stimulates insulin release from the pancreas. While GLP-1 receptor agonists (GLP-1 RAs) have traditionally been utilized to address insulin resistance, their potential application in treating polycystic ovary syndrome (PCOS) has recently garnered attention. This study aimed to investigate the therapeutic efficacy of GLP-1 RAs use for weight loss in women diagnosed with PCOS. We conducted a scoping review following the Joanna Briggs Institute (JBI) methodology and adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our investigation delved into the clinical effects experienced by women of diverse racial and ethnic backgrounds with PCOS who were prescribed GLP-1 RAs for weight loss. Peer-reviewed articles from Ovid Medline, Web of Science, CINAHL, Cochrane CENTRAL, SCOPUS, and ClinicalTrials.gov spanning from 2012 to 2023 were scrutinized. After eliminating duplicates, 811 articles were identified, and ultimately, eight met the eligibility criteria for inclusion. All studies were published in English and exhibited wide geographic diversity. The included studies uniformly reported reductions in weight and body mass index (BMI) among patients who were prescribed GLP-1 RAs, specifically liraglutide or exenatide. Additionally, evidence pointed towards improvements in anthropometric parameters (MF1) (including total body weight, BMI, reduction in waist circumference, and total fat percentage), glucose homeostasis, cardiovascular inflammatory markers (midregional pro-atrial natriuretic peptide (MR-proANP) and mid-regional pro-adrenomedullin (MR-proADM)), rates of pregnancy, and menstrual regulation. However, findings regarding the impact of GLP-1 RAs on lipid profiles were inconsistent. Although some short-term adverse effects were noted, long-term effects of GLP-1 RAs use remain undetermined. GLP-1 RA use demonstrated promising clinical outcomes for women with PCOS, including reduced BMI, improved metabolic parameters, menstrual regularity, and increased rates of natural pregnancy. While the current evidence is encouraging, further research is warranted to elucidate both short- and long-term adverse effects of GLP-1 RA therapy for PCOS.


Introduction And Background
Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders of female reproduction, affecting 6-13% of women of childbearing age [1,2].In the United States, the economic burden of PCOS was estimated at $8 billion annually in 2020, when considering pregnancy-related and long-term morbidities [3].Common characteristics of this syndrome include infertility, metabolic syndrome, chronic oligomenorrhea, as well as signs and symptoms of hyperandrogenism, including hirsutism, acne, and male-pattern hair loss [4].Persistent hyperandrogenemia is associated with impairments in the hypothalamic-pituitary-ovary (HPO) axis, leading to luteinizing hormone (LH) hypersecretion, aberrant oocytes, and follicular maturation, contributing to menstrual dysregulation [5].Although the Rotterdam criteria have been proposed as a tool for diagnosis (presence of two: androgen excess, ovulatory dysfunction, or polycystic ovaries), metabolic rearrangements are an important component of the pathophysiology of PCOS that can provide targetable therapeutic avenues to ameliorate the burden of this disease [6,7].
Insulin has been proposed as a significant factor in the pathophysiology of PCOS given that the effects of this hormone are contributory to steroid metabolism [8].Actions of insulin are propagated by insulin receptors found in tissues of the HPO axis as well as steroidogenic tissues, including the ovary adrenal cortex [5].Women with a PCOS diagnosis have significant insulin resistance [9].Although disordered insulin action is independent of obesity in PCOS, increased body mass index (BMI) exacerbates insulin resistance, leading to excessive androgen production by the liver and adrenal cortex as well as decreased hepatocyte sexhormone binding globulin (SHBG) production and metabolic dysfunction in peripheral tissues, such as skeletal muscle and adipose tissue [5,10].
It has been shown that 50% of patients with a PCOS diagnosis are overweight and obese [7,11] given that the insulin resistance implicated in the pathophysiology of this syndrome predisposes women to metabolic derangements such as hyperinsulinemia, hyperglycemia, impaired glucose tolerance, and dyslipidemia [12].Metabolic syndrome is a significant risk factor for the development of chronic systemic diseases that affect almost every organ system, such as type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) [12][13][14].Although the first-line interventions involve lifestyle measures [6,15] to promote weight loss and improve insulin resistance, the development and clinical use of targetable pharmacological interventions has become of interest to attain optimal therapeutic results, especially for women with obesity and PCOS.
Glucagon-like-peptide-1 (GLP-1) is a regulatory GI incretin hormone that is secreted in response to oral glucose intake and stimulates the release of insulin from pancreatic beta cells [16][17][18].Because GLP-1 secretion has an incretin mechanism that is independent of plasma glucose concentration, pharmacologic analogs have been developed to improve glycemic efficiency in individuals who have impaired glucose tolerance and type 2 diabetes (T1DM) [13].Various studies have shown that GLP-1 receptor agonists (GLP-1 RAs) increase post-prandial insulin release and inhibit glucagon secretion, all without the risk of hypoglycemia [19].Moreover, it has been reported that the use of GLP-1 RAs resulted in weight loss via the hormone's effects on appetite reduction, increased satiety, and significant control of plasma lipid profiles [20,21].
The serendipitous weight loss effects of semiglutide have prompted a robust investigation to conclude its significance as a therapeutic for weight management.Currently, semaglutide is used as an adjunct to lifestyle interventions for the treatment of T2DM and for reducing the risk of cardiometabolic events in patients with cardiovascular disease and T2DM [22].Although common therapeutics used as adjunct therapies for the management of metabolic syndrome in PCOS include metformin, thiazolidinediones, inositols, dipeptidyl peptidase-IV (DPP-IV) inhibitors, and sodium-glucose cotransporter-2 inhibitors (SGLT-2), the potential utility of GLP-1 RA use remains understudied [7].Given that these therapeutics have demonstrated efficacy in improving hyperlipidemia, promoting weight loss, and reducing glycated hemoglobin levels, the implementation of GLP-1 RA could lead to improved outcomes in the management of PCOS [7].
Despite the growing popularity and promising outcomes of GLP-1 RAs as weight-loss adjuncts, there is a need for an examination of the available evidence to determine the safety and efficacy of these pharmacotherapies in patients with PCOS [23][24][25][26].We conducted a scoping review to provide a summary of the current available evidence regarding the relevance of GLP-1 agonist use for weight loss in patients diagnosed with PCOS.To our knowledge, no scoping reviews have been conducted on this topic.

Review Methods
We conducted a scoping review in accordance with the methodology outlined by The Joanna Briggs Institute Scoping Review Methodology (JBI) [27].
Our study focused on evaluating the correlation between GLP-1 utilization in female patients formally diagnosed with PCOS.The study's search strategy was developed collaboratively by the first (MF), second (TS), and third (GH) authors along with a medical research librarian.Peer-reviewed articles that were published in English between 2012 and September 2023 were selected.Exclusion criteria were applied to studies involving children (≤ 18 years of age) or postmenopausal women over the age of 65.Additionally, papers were excluded if they did not align with the conceptual framework of our study.
To ensure comprehensive coverage, the initial search was intentionally broad, aiming to minimize the risk of overlooking potentially relevant studies.The foundation of the search strategy was established through an analysis of key terms related to PCOS and GLP-1 receptor agonists, extracted from MeSH and relevant articles in Embase.Authors five through nine then translated this base search strategy to four additional databases: Ovid Medline, Web of Science, CINAHL, and ClinicalTrials.gov.Gray literature was not included in the search process.The Embase search strategy can be found in Appendix 1.
Authors one (MF) and two (TS) conducted a screening of titles and abstracts based on our pre-defined criteria.Any discrepancies were addressed by the third (GH) author and, when needed, were further resolved through discussion amongst authors one through three until a consensus was reached.Full-text screening followed the same approach.The primary author (MF) developed a thematic framework charting form to guide the extraction of variables.Authors five through nine were responsible for completing the data extraction of selected studies, which included details such as study design, recruitment/data collection period, country, setting, sample size and characteristics, study objectives, and outcomes.Relevant data from the studies were entered into a Microsoft Excel (Microsoft Corporation, Redmond, Washington, United States) extraction form for further analysis.
A pair of authors (authors five through nine) independently utilized the Joanna Briggs Institute Appraisal Tools [28,29] to critically appraise each selected study based on its specific methodologies and screen for potential risk of bias.The studies were categorized into risk levels: scores below 50% indicating high risk, scores between 50%-70% indicating moderate risk, and scores above 70% indicating low risk (Appendices 2 and 3).
Data from each cell of our framework underwent analysis to comprehensively describe the studies and findings regarding GLP-1 use among patients with PCOS.
Several studies evaluated the effect of GLP-1 RA on biochemical parameters that are indicative of metabolic health.Across the studies, both EXE and LIRA therapies were associated with reductions in inflammatory markers, including C-reactive protein (CRP) [30,33].Additionally, improvements in endothelial function and markers of cardiovascular health, such as reduced ICAM-1, p-selectin, e-selectin, serum triglycerides, and baseline thrombogenic potential, were observed following treatment with these medications [30].
Discrepancies in the therapeutic effects of GLP-1 RA use on lipid profiles and sensitivity were evident across the included studies.While some studies reported no significant impact on total cholesterol, low-density lipoproteins (LDL), and high-density lipoproteins (HDL) levels following EXE and LIRA interventions, triglyceride levels exhibited the most variability among the lipid panel components [30][31][32]34].Specifically, certain studies found no change in triglyceride levels after pharmacological interventions, whereas others reported significant improvements following GLP-1 receptor agonist use [31,32,34,37].Additionally, blood glucose parameters were addressed in several studies.Some studies demonstrated improved glucose tolerance and insulin homeostasis with EXE compared to metformin interventions, along with reductions in fasting glucose and HbA1c levels [33].Similarly, LIRA therapy resulted in improved mean blood glucose and insulin response following a 32-week intervention [31].However, there were conflicting findings regarding fasting insulin levels, as some studies reported no significant effect [34].
Across the studies, hormonal profiles were examined in relation to GLP-1 receptor agonist interventions.
LIRA treatments were consistently associated with decreased testosterone levels and reductions in sex hormone-binding globulin (SHBG) levels [31,32,34].However, findings regarding the effects of EXE therapy on testosterone levels were inconsistent, with some studies reporting no significant decrease and others noting an increase in SHBG levels [33].

Discussion
PCOS presents multifaceted challenges to women's health, affecting fertility, metabolic well-being, and cardiovascular risk [38].Exploring novel pharmacological interventions is paramount in addressing this complex condition.In this scoping review, we examined the potential of GLP-1 RAs in managing PCOS, focusing on clinical, biochemical, and adverse effect profiles.The selected studies provided valuable insights into the use of long-acting GLP-1 RAs, including LIRA and EXE, across diverse geographic locations and study designs [30][31][32][33][34][35][36][37].The findings of this review underscore the growing interest in repurposing GLP-1 RAs beyond their traditional indication for T2DM to address metabolic and hormonal dysregulation and PCOS.
Our review highlighted the favorable effects of GLP-1 RA interventions on clinical parameters, particularly BMI and weight reduction [31,37].Anthropometric improvements, such as reduction in waist circumference and total fat percentage, were consistently observed following GLP-1 RA therapy [31,37], indicating potential benefits for cardio-metabolic health in PCOS patients.For instance, Dawson et al. reported a 3% reduction in total body weight among PCOS patients who received EXE therapy [30], while Tang et al. reported similar findings, supporting a significant decrease in body weight, BMI, fat content, and waist and hip circumference following EXE intervention [37].
While our study revealed inconclusive gaps in the impact of GLP-1 RAs on lipid profiles, improvements in glucose homeostasis were evident across most studies [30,[33][34][35].Liu et al. explored the effects of EXE therapy, highlighting improved glucose tolerance in PCOS.These findings reinforce the therapeutic potential of GLP-1 RAs in addressing metabolic dysregulation among PCOS patients.
Moreover, the utilization of GLP-1 RAs has been associated with enhancements in inflammatory and vascular markers, indicative of improved cardiovascular function [30,33].Reduced levels of CRP and improved endothelial function suggest potential cardio-protective effects of GLP-1 RAs in PCOS patients [30].Dawson et al. demonstrated enhanced endothelial function and decreased serum triglycerides following EXE treatment [30], while Frossing et al. observed reductions in cardiovascular risk biomarkers, such as MR-proANP and MR-proADM, following LIRA therapy [32], further bolstering the cardiovascular advantages of GLP-1 RA administration for PCOS.
In addressing the reproductive manifestations of PCOS, GLP-1 RA interventions have displayed encouraging results in promoting menstrual regularity and fertility outcomes [31,33].Reductions in testosterone levels and an increase in SHBG following GLP-1 therapy indicate potential advantages for restoring hormonal equilibrium among PCOS patients [31][32][33][34][35].For instance, Liu et al. reported improvements in menstrual cycle frequency and rates of spontaneous pregnancy following EXE treatment [33], while Nylander et al. observed improvements in ovarian dysfunction and enhanced bleeding regularity following LIRA intervention [34,35].
Despite these promising findings, caution is warranted regarding the long-term adverse effects of GLP-1 RAs, including gastrointestinal disturbances and hypoglycemia [33][34][35][36].In clinical practice, gastrointestinal disturbances, including nausea, vomiting, and diarrhea, are the most common side effects and reasons for medication discontinuation [39], with pancreatitis being the most frequently reported adverse reaction associated with LIRA and EXE [40].While LIRA is FDA-approved for chronic weight management, other GLP-1 RAs, such as EXE, used for this purpose are currently prescribed off-label.Further research is needed to elucidate their safety profile.Comprehensive assessments of the adverse effect profiles of GLP1-RAs, including gastrointestinal disturbances and hypoglycemia, are imperative for informing clinical decisionmaking and optimizing patient care and PCOS management.
Future research endeavors should focus on conducting larger, placebo-controlled trials to establish the efficacy and safety of GLP-1 RAs in PCOS populations.Longitudinal studies are needed to assess the durability of weight loss and metabolic improvements associated with GLP-1 therapy, as well as their impact on cardiovascular outcomes in the long term.
Furthermore, investigating the mechanistic underpinnings of GLP-1 effects on reproductive hormones and fertility outcomes in PCOS is crucial for understanding their potential role in reproductive medicine.Recent research on second-line anti-diabetic medications, including GLP-1 RAs, suggests no increased risk of major congenital malformations with periconceptional maternal use, yet further evidence is required to confirm their safety throughout pregnancy [41].Additionally, our findings, which show conflicting results regarding the effects of GLP-1 RAs on lipid profiles, underscore the need for more robust studies to clarify their impact on cardiovascular risk factors in PCOS [31,32,34,37].
Our study has several limitations that warrant acknowledgment.The limited number of studies included in this scoping review may restrict the generalizability of our findings.Additionally, the exclusion of studies involving combination therapies and the non-diabetic PCOS population may have influenced the comprehensiveness of our results.Moreover, the recent FDA approval of some GLP-1 RAs for weight management may have limited the availability of eligible studies within our time frame.Furthermore, our reliance on peer-reviewed original articles may have overlooked relevant gray literature and unpublished data.Despite these limitations, our scoping review provides valuable insight into the current landscape of GLP-1 RA use in PCOS and highlights avenues for future research to address existing knowledge gaps and optimize patient care.

Conclusions
In conclusion, while GLP-1 RAs hold promise as a therapeutic option for PCOS management, further research is warranted to validate their efficacy, safety, and long-term outcomes in this population.As PCOS continues to pose significant clinical challenges, exploring innovative pharmacological strategies remains crucial in improving outcomes and quality of life for affected individuals.

FIGURE 1 :
FIGURE 1: PRISMA flow diagram PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses from 67 participants (32 with PCOS, 35 controls) were collected before and after EXTE assays measured blood lipids, glucose, and insulin, including TC, TG, FFA, LDL-C, and HDL-C.Metabolite changes were detected via NTGC-MS, alongside clinical biochemical observations.with LIRA was initiated, and variables such as the date of the first prescription, age, initial body weight, height, weight loss at follow-up, and dose were recorded.The treatment duration extended from the date of the first prescription until either the discontinuation of treatment or the date of the last recorded weight loss for patients still undergoing treatment during the study period 08/2010underwent a 4-month EXE regimen with adherence tracking, alongside baseline and endpoint clinical and biochemical evaluations encompassing serum testosterone, SHBG, FAI, lipid profile, insulin resistance, and liver function.Endothelial function was gauged via RH-PAT, while clot structure and fibrinolysis were analyzed using turbidity and lysis assays.EXE caused a 3% reduction in weight, in a 2:1 ratio to receive either LIRA or placebo; for every two participants who received LIRA, one participant received the placebo.Data collection methods included measuring body weight with participants wearing light clothes on a calibrated scale, assessing waist circumference between the lowest rib and the iliac crest, and measuring blood pressure after ten minutes of rest in the sitting position.Blood samples were collected in the morning -hour overnight fast, and a 75g oral glucose tolerance test was performed with blood samples collected at 0, 30, 60, and 120 minutes.Additionally, biomarkers were analyzed before the randomization key was broken using an automated immunofluorescence assay, and MRI scans were performed to measure volumes of visceral and subcutaneous to receive either EXE (n=88) or metformin (MET) (n=88) for the first 12 weeks.Then all patients were treated with MET alone during the second 12 weeks.Metabolic parameters were observed at 0 and 12 weeks, and the rate of pregnancy was tracked during the second 2:1 to receive LIRA (n=42) or placebo (n=21), with data collected including body weight, waist circumference, blood pressure, fasting blood samples, and a glucose tolerance test.Biomarkers (MR-proADM, MR-proANP, and copeptin) were analyzed before unblinding, and MRI scans were conducted to measure adipose tissue volumes.elaborate on total numbers in control vs placebo.2:1 to receive LIRA (n=48) or placebo (n=24).Changes in plasminogen activator inhibitor-1 (PAI-1) levels and thrombin generation test parameters, along with anthropometric, metabolic, and endocrine measurements (SHBG, insulin, testosterone) were collected at baseline and follow-up visits.

TABLE 3 : Joanna Briggs Institute (JBI) checklist for randomized controlled trials (RCT) critical appraisal tool for use in systematic reviews Appendix 3
Joanna Briggs Institute (JBI) Checklist for Quasi-Experimental Studies Critical Appraisal Tool for Use in Systematic Reviews