Exploring Better Therapies For Polycystic Ovary Syndrome: The Role Of Anti-Obesity Medications
Overview
This systematic review and meta-analysis aimed to assess the efficacy of anti-obesity agents in addressing hormonal, reproductive, metabolic, and psychological outcomes in women with polycystic ovary syndrome (PCOS), with the objective of informing updates to the International Evidence-based Guideline on PCOS in 2023. The search encompassed databases including Medline, EMBASE, PsycInfo, and CINAHL up to July 2022, focusing on newer agents within the past decade. Eleven trials, comprising 545 participants in the intervention arms and 451 participants in control arms, yielding 12 comparisons, were included in the analysis.
Descriptive analyses indicated that most anti-obesity agents demonstrated improvements in anthropometric outcomes. Notably, liraglutide, semaglutide, and orlistat exhibited superior efficacy over placebo for anthropometric outcomes. Meta-analyses were feasible for two comparisons: exenatide versus metformin, and orlistat in combination with a combined oral contraceptive pill (COCP) versus COCP alone.
The meta-analysis did not reveal significant differences between exenatide and metformin for various outcomes, except for lower fasting blood glucose levels observed with metformin compared to exenatide. Similarly, the combination of orlistat with COCP did not demonstrate substantial improvements in metabolic outcomes compared to COCP alone, as evidenced by fasting insulin levels.
It is worth noting that the available published data on the effects of anti-obesity agents in women with PCOS are limited. Hence, further research addressing the role of these agents in PCOS management is deemed a critical priority for future investigations. This underscores the necessity for robust clinical trials to elucidate the potential benefits and risks associated with the use of anti-obesity agents in the context of PCOS.
Introduction
Polycystic ovary syndrome (PCOS) represents a multifaceted disorder with far-reaching metabolic and reproductive implications for women of childbearing age. At its core lies a complex interplay of hormonal dysregulation involving the hypothalamus, pituitary, and ovaries, coupled with heightened insulin levels and resistance, which foster excess androgen production. These hormonal imbalances manifest clinically with a spectrum of symptoms encompassing irregular menstrual cycles, hyperandrogenism, and polycystic ovarian morphology.
Over the past two decades, the diagnostic criteria for PCOS have evolved, transitioning from the Rotterdam Criteria to the more refined International Evidence-based Guideline PCOS criteria. This updated framework allows for a more precise delineation of PCOS, incorporating parameters such as Anti-Mullerian Hormone levels as alternatives to traditional ultrasound assessments of ovarian morphology.
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The association between PCOS and obesity is notable, with a bidirectional relationship evident in genetic studies and epidemiological observations. While obesity exacerbates PCOS symptoms, including menstrual irregularities and hyperandrogenism, PCOS itself predisposes individuals to weight gain and obesity-related comorbidities such as diabetes, cardiovascular disease, and sleep apnea.
Effective weight management is thus a cornerstone of PCOS treatment, with lifestyle modifications—such as dietary changes and increased physical activity—constituting primary interventions. However, implementing and sustaining these lifestyle adjustments can pose significant challenges, often necessitating adjunctive pharmacotherapy to optimize outcomes.
A range of pharmacological agents has been investigated for their potential in PCOS management. Among these, glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have garnered attention for their dual benefits in promoting weight loss and improving glycemic control, particularly in individuals with a higher body mass index (BMI). Similarly, orlistat, a pancreatic lipase inhibitor, offers a mechanism to limit dietary fat absorption, aiding in weight reduction.
Additionally, centrally acting anti-obesity medications, such as phentermine and topiramate, target appetite regulation and energy expenditure through modulation of neurotransmitter pathways in the hypothalamus. Metformin, a widely used agent in diabetes management, has also demonstrated utility in PCOS treatment, albeit with limited efficacy in promoting weight loss.
Despite the array of pharmacological options available, their specific roles and effectiveness in PCOS management remain subjects of ongoing investigation. This systematic review and meta-analysis aim to provide critical insights into the efficacy of anti-obesity pharmacotherapies, both individually and in combination, in addressing the hormonal, reproductive, metabolic, and psychological facets of PCOS. By elucidating the potential benefits of these agents, this research endeavor seeks to inform clinical practice and guide the development of evidence-based guidelines for PCOS management in adolescents and adults.
Methods
- Participants:
Inclusion Criteria:
– Individuals diagnosed with polycystic ovary syndrome (PCOS) according to Rotterdam, original National Institutes of Health (NIH), or Androgen Excess and Polycystic Ovary Syndrome society (AE-PCOS) criteria, irrespective of age, ethnicity, or weight.
Exclusion Criteria:
– Studies focusing exclusively on populations without a confirmed diagnosis of PCOS.
– Trials lacking clarity regarding diagnostic criteria for PCOS.
- Intervention:
Inclusion Criteria:
– Administration of anti-obesity pharmacological agents for a minimum duration of 3 months.
– Acceptable agents include, but are not limited to, orlistat, glucagon-like peptide 1 receptor agonists (GLP-1 RAs), phentermine/topiramate, lorcarserin, or naltrexone/bupropion.
– Administered either alone or in combination with lifestyle modifications, metformin, the combined oral contraceptive pill (COCP), or anti-androgens.
– Exclusion Criteria:
– Studies not involving the specified anti-obesity pharmacological agents.
– Administration duration of less than 3 months.
- Comparison:
Inclusion Criteria:
– Comparisons against placebo or any other intervention listed in the intervention criteria.
Exclusion Criteria:
– Trials lacking appropriate comparison groups.
- Outcomes:
Inclusion Criteria:
– Assessment of hormonal, metabolic, lipid, psychological, or anthropometric outcomes.
– Evaluation of adverse effects.
– Exclusion Criteria:
– Studies lacking relevant outcome measures.
– Trials not reporting on adverse effects.
- Study Design:
Inclusion Criteria
– Only randomized controlled trials (RCTs) are eligible for inclusion.
– Crossover trials are included only for the phase preceding the crossover.
Exclusion Criteria:
– Quasi-randomized trials.
– Conference abstracts.
– Trials not published in English.
- Integrity Assessment:
– Inclusion Criteria:
– Studies classified as low risk for integrity concerns based on the Trustworthiness in Randomised Controlled Trials (TRACT) checklist.
– Exclusion Criteria:
– Studies classified as moderate or high risk for integrity concerns.
– Studies with unresolved integrity concerns after contact with authors.
Data Analysis
In the systematic review, several outcomes were deemed critical for evaluating the efficacy of anti-obesity pharmacological agents in managing polycystic ovary syndrome (PCOS). These critical outcomes included the modified Ferriman-Gallwey (mFG) score, free androgen index (FAI), homeostatic model assessment of insulin resistance (HOMA-IR), 2-hour glucose after a 75-gram oral glucose tolerance test (OGTT), and body mass index (BMI). Other outcomes were considered important but not critical.
Data on these outcomes were extracted primarily from original intention-to-treat results, with per-protocol results used if intention-to-treat data were unavailable. Mean differences (MD) and 95% confidence intervals (CIs) were reported for trials using the same assessment methods, with conversions to standardized units as needed. For trials employing different assessment methods, standardized mean differences (SMD) and 95% CIs were reported.
Assessment of heterogeneity was conducted using the I2 statistic, with outcomes pooled across individual studies using random-effects models. Statistical analyses were performed utilizing Review Manager software. Although subgroup analyses were planned to explore differences among post-menopausal individuals, adolescents versus adults, and different BMI categories, these analyses could not be conducted due to the limited number of trials included in the review.
Results
The study selection process involved identifying 782 citations, with 675 remaining after removing duplicates. Following title and abstract screening, 647 citations were excluded, leaving 28 full-text manuscripts for eligibility assessment. Among these, six manuscripts were excluded, and five are awaiting classification, resulting in the inclusion of 17 manuscripts representing 11 trials and 996 participants.
Most of the trials were conducted in China, followed by the United States, with smaller numbers in Slovenia, Iran, and Denmark. The sample sizes varied, with a mean of 91 participants per study. The inclusion criteria generally targeted adults with PCOS and a BMI in the overweight or obese range. Various anti-obesity pharmacological agents were trialed, either alone or in combination with other interventions such as lifestyle modifications, metformin, or the combined oral contraceptive pill (COCP).
Regarding comparisons, four studies were placebo-controlled, while others used metformin, COCP and lifestyle, or other combinations as comparators. The outcomes assessed included anthropometric measurements, metabolic parameters, lipid profiles, and reproductive outcomes. Most trials collected data on weight, BMI, waist circumference, fasting glucose, insulin levels, and androgen-related markers. However, no studies collected data on quality of life or psychological outcomes.
The risk of bias assessment revealed several concerns, particularly regarding blinding of participants and personnel, allocation concealment, and reporting bias. Meta-analyses were conducted for some comparisons, such as exenatide versus metformin and orlistat+lifestyle,COCP versus lifestyle,COCP, while narrative synthesis was provided for others due to data limitations.
Overall, the findings suggested that metformin was superior to exenatide in certain metabolic outcomes, although exenatide showed advantages in other parameters such as weight, BMI, and waist circumference. Gastrointestinal adverse events were more common with exenatide. However, further research is warranted to elucidate the comparative effectiveness and safety of various anti-obesity pharmacological agents in the management of PCOS.
Conclusion
This meta-analysis assessed the impact of anti-obesity agents on various outcomes in individuals with polycystic ovary syndrome (PCOS), including hormonal, metabolic, anthropometric, and reproductive parameters. The findings indicate that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as exenatide, liraglutide, and semaglutide demonstrate varying efficacy in weight reduction within a 12-week timeframe, which correlates with improvements in metabolic and reproductive aspects of PCOS. Orlistat showed superiority over the combined oral contraceptive pill (COCP) alone in certain anthropometric outcomes but not in metabolic parameters. No significant differences were observed between exenatide and phentermine/topiramate regarding anthropometric measurements, biochemical hyperandrogenism, metabolic indices, and lipid profiles. However, it’s important to note that all anti-obesity agents resulted in higher adverse event rates compared to controls, including metformin.
The interest in using GLP-1 RAs in PCOS has surged due to their overall effectiveness in weight reduction. Previous narrative reviews supporting their use in PCOS primarily relied on single-center randomized controlled trials (RCTs) and observational studies. Recent meta-analyses comparing GLP-1 RAs versus metformin in PCOS included a limited number of RCTs but concluded that GLP-1 RAs, with or without metformin, offer benefits in terms of metabolic, reproductive, and anthropometric parameters.
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