The dual impact of GLP-1 receptor agonists on metabolic and reproductive health in polycystic ovary syndrome: insights from human and animal trials

Abstract

Polycystic ovary syndrome (PCOS) is a prevalent disorder in the modern world, affecting around 6%–20% of females of childbearing age. Hormonal and metabolic symptoms vary over time but often arise throughout puberty. Treatment includes lifestyle interventions as a first line of treatment. In certain cases, specific medications may be considered. However, there is a growing interest in using Glucagon-like Peptide-1 Receptor Agonists (GLP-1RAs) in PCOS due to their efficacy in weight loss, insulin resistance, and heart health. Aside from the metabolic role of GLP-1RAs, which aids in the relief of PCOS symptoms, there is also the possibility of direct involvement in reproductive health in PCOS, including its role in the hypothalamic-gonadal axis, menstrual irregularity, ovulation, ovarian morphology, anti-inflammatory properties, and fertility. This review discusses the latest data on GLP-1RAs’ metabolic and reproductive health benefits in PCOS. Moreover, this article covers pharmaceutical interactions and synergistic effects of drugs, including metformin and other medications, with GLP-1RAs. It also conveys an overview of recent clinical trials utilizing GLP-1RAs to treat PCOS.

Introduction

Polycystic ovary syndrome (PCOS) is a widespread endocrine and metabolic ailment occurring in about 6%–20% of females of childbearing age. ¹ Females are found to have multiple ovarian cysts, defined by a follicle number per ovary ⩾20, ovarian volume ⩾10 mL, or follicle number per section ⩾10 in at least one ovary. ² These cysts are formed in the ovarian follicles due to hormonal imbalance, specifically hyperandrogenism, which is a key manifestation of PCOS, along with ovulatory dysfunction and altered polycystic ovarian morphology.^3,4 Currently, PCOS is diagnosed using the 2023 international evidence-based guidelines, built based on the 2003 Rotterdam criteria. ² For a diagnosis to be made, it should include two of the three following: (i) hyperandrogenism, whether clinical or biochemical, (ii) ovulatory dysfunction (this also includes cases of regular cycles where anovulation is evaluated by measuring progesterone levels), and (iii) polycystic ovaries on ultrasound, the latter could be replaced by raised levels of anti-Müllerian hormone (AMH) in adults. ² Moreover, PCOS may present as an irregular cycle, defined by an abnormal duration of <21 or >35 days or several cycles <8 per year. ²

Regarding the pathogenesis of PCOS, its manifestation results from the interaction between potent environmental factors and predisposing genetic background, leading to different clinical phenotypes. ⁵ Women with PCOS can experience a wide range of clinical manifestations that impact their reproductive system (infertility, hyperandrogenism, and hirsutism), metabolism (insulin resistance (IR), altered glucose tolerance, type 2 diabetes mellitus (T2DM), and increased cardiovascular risks), and psychological state (stress, depression, and a lower quality of life).^3,6 Additionally, acne, alopecia, and hirsutism are common manifestations of hyperandrogenemia (excess androgens), which is the key biochemical feature of PCOS. ⁷ Due to abnormally functioning ovaries and adrenals, the levels of androgens are further increased, leading to increased levels of free testosterone (FT). ⁷

Normally, the release of follicular-stimulating hormone (FSH) and luteinizing hormone (LH), which regulate estrogen and androgen production in the ovaries, respectively, is controlled by gonadotropin-releasing hormone (GnRH). ⁸ However, hyperinsulinemia as a compensatory response to IR plays a central role in the pathogenesis of hyperandrogenism in PCOS. ⁹ Insulin acts synergistically with LH in the ovarian theca, stimulating them to undergo hyperplasia and accumulate fluid.^9,10 It forms cystic structures that give the ovaries their characteristic “string of pearls” appearance, stimulating excess androgen production.^9,10 It may also influence the neuroendocrine axis by increasing GnRH secretion, which preferentially stimulates LH over FSH, further promoting increased androgen levels. ⁸ Additionally, insulin suppresses hepatic production of sex hormone binding globulin (SHBG), a glycoprotein responsible for regulating the bioavailability of testosterone, leading to an increase in FT levels.^9,10 These combined ovarian and extra-ovarian effects position hyperinsulinemia as a major driver of androgen excess in PCOS.^9,10

Hyperandrogenism is a common clinical feature shared between multiple diseases with different pathophysiology and etiology, such as PCOS and non-classic congenital adrenal hyperplasia, caused by 21-hydroxylase deficiency. ¹¹ This overlap raises multiple questions concerning the involvement and contribution of the adrenal glands in the excess androgen production observed in PCOS. ¹² Recent studies have shed light on the role of 11-oxygenated androgens. ¹³ These adrenal-derived steroids are structurally and functionally similar to testosterone and are considered the predominant circulating unconjugated androgens in PCOS patients. ¹³ The adrenal enzymatic dysfunction leads to the excess of 11-oxygenated androgens, highlighting the shared pathway of hyperandrogenism in both disorders. ¹⁴

PCOS, a polygenic disorder characterized by an inflammatory state and imbalanced steroid levels, mainly triggered by lifestyle and environmental factors. ³ It is considered the most common endocrine disorder in females of reproductive age and one of the major causes of infertility, as in this case, 70%–80% of women with this condition suffer from infertility.^15,16 More readily available biochemical tests and ultrasound have facilitated the diagnosis of PCOS in affected females. ³

Many interventions are now being adopted to surpass or reverse the pathologic effects of PCOS, such as metformin, a biguanide drug used for lowering blood glucose in diabetic patients, which is recommended for adults with a body mass index (BMI) ⩾25 kg/m² for metabolic outcomes, such as improvement of IR, lipid profile, and glucose profile.^2,3,17 It can also be useful in adolescents for cycle regulation, through enhancing androgen levels, normalizing LH/FSH levels, and decreasing LH levels, if they have PCOS or are at risk.^2,3,18 Additionally, thiazolidinediones (TZDs), a class of antidiabetic medications, have been used off-label in the treatment of PCOS by managing insulin levels and several reproductive functions, such as ovulation. ¹⁹ TZDs improve ovulation by reducing IR, which helps to suppress ovarian androgen production and restore normal function of the hypothalamic-pituitary-ovarian axis. ¹⁸ Moreover, oral contraceptive pills (OCPs) are recommended for women of reproductive age to treat hirsutism and irregular menstrual cycles.^2,3 When these agents fail 6 months post-administration, anti-androgen pharmacological agents, such as spironolactone, cyproterone acetate (CPA), flutamide, and finasteride, can be useful in treating hirsutism in women with PCOS.^2,3 However, the currently maintainable and recommended treatment for all PCOS patients remains lifestyle interventions (exercise alone or combined with multicomponent diet and behavioral strategies) that help in reducing exposure to inflammatory particles, thus decreasing immune reactions.^2,3 Moreover, weight reduction appears to improve both reproductive and metabolic parameters in women with PCOS. ¹⁶ Unfortunately, inadequate patient adherence can undermine the potential benefits of this approach. ²⁰ Lifestyle interventions, such as setting goals, self-control, and problem-solving, can improve weight management, health, and overall quality of life in women with PCOS. ² That is when comprehensive behavioral therapy comes in handy to enhance support and adherence to pharmacological agents and lifestyle changes. ²

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are a family of drugs licensed by the Food and Drug Administration (FDA) to treat T2DM and, in certain circumstances, obesity by imitating incretin action.^20,21 The GLP-1 receptors are highly expressed in the stomach, brain, pancreas, and cardiovascular systems. ²² Therefore, GLP-1RAs primarily regulate the function of these tissues. ²² In the pancreas, they promote glucose-dependent insulin release, reducing the risk of hypoglycemia and suppressing glucagon secretion during hyperglycemia, thereby improving the overall glucose balance by limiting hepatic glucose production.^23,24 Moreover, significant weight loss in patients with PCOS or overweight was seen after the use of GLP-1RAs as a monotherapy or combined with metformin, showing the beneficial metabolic role of these analogs. ²⁰ The administration of GLP-1RAs is useful in some cases, especially when diet and exercise fail to attain therapeutic benefits. ¹⁶

The first drug to enter the market was exenatide, which was FDA approved in 2005. ²⁵ Since then, several other GLP-1RAs have been developed, differing mainly in their duration of action. These include short-acting forms like exenatide and lixisenatide, as well as long-acting ones such as liraglutide, dulaglutide, and semaglutide. ²⁵ Several clinical trials and meta-analyses have been done to compare the different drugs, showing that long-acting agents are more effective in glycemic control by reducing fasting plasma glucose (FBG) and hemoglobin A1c (HbA1c), whereas short-acting agents may be more beneficial in managing postprandial glucose levels. ²⁵

The articles included in this narrative review were selected based on their relevance to the topic, rather than through a systematic methodology. This review provides an in-depth analysis of the various metabolic and reproductive benefits of GLP-1RAs in PCOS. Moreover, this review discusses pharmaceutical interactions and synergistic effects of drugs, including metformin and other medications, with GLP-1RAs. It also conveys an overview of recent human and animal clinical trials investigating the use of GLP-1RAs in the treatment of PCOS.

Metabolic benefits of GLP-1RAs in PCOS

Over the last decade, incretin modulators have emerged as an intriguing treatment option for obesity and T2DM. ²⁶ Among these, GLP-1RAs are increasingly being used to treat PCOS due to their efficacy in improving insulin sensitivity, encouraging weight reduction, and improving cardiovascular health, as well as delivering a variety of metabolic advantages.^26,27

Metabolic regulation

In PCOS, IR is highly prevalent, accounting for around 75% of cases. ²⁸ It is very common in obese (93.9%), overweight (77.5%), and even in normal-weight PCOS patients (59.3%). ²⁹ It is defined as an impaired cellular response to insulin, caused by a defect in the insulin receptor-related signaling pathway, and is commonly associated with high visceral fat, persistent inflammation, and reactive oxygen species (ROS). ²⁸ This leads to the increased demand for insulin to maintain metabolic, reproductive, and mitogenic functions, due to impaired insulin-responsive glucose transporter, lower glycogen production, and suppression of hepatic gluconeogenesis.^28,30 IR has a crucial impact in exacerbating oligomenorrhea and hyperandrogenism in PCOS, due to the hyperinsulinemia, which enhances the ovarian androgen secretion.^20,31 Antidiabetic medications are known to be used in PCOS; among these, GLP-1RAs stimulate insulin secretion in a glucose-dependent manner from pancreatic islets, increasing postprandial insulin and inhibiting glucagon secretion.^16,32,33 Elkind-Hirsch et al. ³⁴ showed in a study group of women with PCOS treated with a high dose of liraglutide (3.0 mg/day) for 32 weeks, a significant improvement in FBG, homeostatic model assessment of insulin resistance (HOMA-IR), post-load glucose levels from an oral glucose tolerance test (OGTT), OGTT-derived insulin sensitivity index, and improved early insulin response to glucose, compared to the placebo group. Also, it has been shown that GLP-1RAs can improve insulin sensitivity, decreasing FBG, triglycerides (TG), and total cholesterol (TC) in young, non-diabetic PCOS patients. ³⁵

Chronic inflammation, exacerbated by excess adipose tissue, particularly visceral adipose tissue, and the pro-inflammatory impact of elevated testosterone levels, is one of the major factors contributing to the development of IR. ³⁶ Compared to normal-weight women, obese females with PCOS exhibit an elevated level of cytokines, inflammatory markers, angiotensin-renin system activity, and plasminogen activator inhibitor-1, along with a decreased level of adiponectin. ³⁶ Hence, by reducing inflammation, decreasing oxidative stress, and modulating lipid metabolism, GLP-1RAs show a significant role in PCOS. ²⁸ Several inflammatory mediators, such as Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), Monocyte Chemoattractant Protein-1, and Nuclear Factor kappa-light-chain-enhancer of activated B cells, together with c-Jun N-terminal kinase activation and macrophage activity in adipose tissue, are decreased by GLP-1RAs in a mouse model^37–40 (Figure 1).

Figure 1.

The inflammatory impact of GLP-1 in a mouse model. The role of GLP-1 release in modulating pancreatic function, inflammatory factors, and the number of macrophages in the adipose tissue by inhibiting glucagon and stimulating insulin.^37–40

Source: Generated with BioRender.

GLP-1, glucagon-like peptide-1.

Additionally, PCOS can lead to impaired hepatic health through fat deposition in the liver due to obesity, causing elevated liver enzymes, nonalcoholic fatty liver disease (NAFLD), cirrhosis, and hepatocellular carcinoma. ⁴¹ GLP-1RAs were proven to be beneficial in hepatic health. ⁴¹ Kahal et al., ⁴¹ in a study of a group of 19 PCOS patients treated with liraglutide, showed a significant reduction in procollagen type 3 amino-terminal peptide (PIIINP), a peptide that serves as a predictor of liver cirrhosis. ⁴¹ Due to the increased incidence of NAFLD in PCOS, where a study conducted by Harsha Varma et al. ⁴² found that 38.3% of women with PCOS had NAFLD, this adds another element to the importance of the usage of GLP-1RAs in women with PCOS. ¹⁶

Weight loss

Overweight (BMI ⩾25 and <30 kg/m²) or obese (BMI ⩾30 kg/m²) women constitute 60%–70% of women with PCOS. ³² Obesity is shown to be associated with the symptoms of PCOS, interfering with ovarian function, ovulation rate, and endometrial receptivity through chronic inflammation and the suppression of the hypothalamic-pituitary-gonadal (HPG) axis. ⁴³ Additionally, obesity may lead to secondary PCOS. ⁴³ Moreover, visceral fat plays a major role in the development of PCOS by causing metabolic disturbances through increased levels of adipokines and fatty acids. ⁴⁴ In a study of 40 women with anovulatory PCOS, waist circumference (WC) was proven to be the best indicator of IR. ⁴⁵

Hence, the reduction of body weight is imperative to decrease and alleviate the reproductive and metabolic symptoms of PCOS. ³² According to the 2023 international evidence-based guideline for the assessment and management of PCOS, it is recommended to abide by a healthy lifestyle, including a healthy diet and/or physical activity, to improve general health, quality of life, body composition, and weight management. ² Moreover, the Polish Society for the Treatment of Obesity published guidelines for the therapeutic goal of weight loss in women with PCOS, which is a weight reduction greater than ⩾5%–15% of the initial body weight over 3–6 months. ⁴⁶ A 0.5 kg weekly loss is also considered optimal. ⁴⁶

GLP-1RAs, such as liraglutide and semaglutide, combined with lifestyle modifications, were approved for weight reduction for individuals with BMI ⩾30 kg/m² or BMI ⩾27 kg/m² with at least one comorbidity associated with obesity (e.g., elevated blood pressure (BP), T2DM, prediabetes mellitus, dyslipidemia, and obstructive sleep apnea) by both the United States FDA and the European Medicines Agency.^47,48 Additionally, GLP-1RAs were proven to be beneficial in other metabolic comorbidities, such as non-alcoholic steatohepatitis and osteoarthritis, where they are being used, although not yet approved.^49,50 Both excess body weight and glycemic levels can be managed with one medicinal prescription of GLP-1RAs. ³²

The importance of these medications lies in the superior weight reduction compared to metformin, besides the metabolic, reproductive, and cardiovascular benefits, as proven by most trials. ²⁷ Liu et al. ⁵¹ showed higher weight reduction (4.29 ± 1.29 vs 2.28 ± 0.55 kg) and fat loss (4.67% ± 0.09% vs 1.11% ± 0.32%) after 12 weeks of exenatide, a GLP-1RA, compared to metformin. This weight loss effect is due to GLP-1RAs’ role in regulating energy expenditure and delaying gastric emptying. ²⁶ In addition to their ability to penetrate the blood-brain barrier, the control of appetite and hunger gives the GLP-1RAs an important role in the management of PCOS. ⁴⁷ Additionally, aside from the 5.6% reduction in body weight, visceral adipose tissue was reduced by 18% in PCOS patients when treated with liraglutide for 26 weeks, in a trial of 72 women. ⁵²

Cardiovascular impact

The recent introduction of GLP-1RAs in diabetes mellitus management has been associated with significant cardiovascular benefits, which extend beyond their primary role in maintaining glucose. ⁵³ Oxidative stress, due to the excessive production of free radicals, is a major event in many vascular pathologies. ⁵³ Some studies proved that GLP-1RAs could reduce the effects of ROS by changing fatty acid oxidation, energy consumption, and glucose metabolism through their effect on the mitochondria. ⁵³ Metabolic syndrome (MetS), defined by criteria such as central obesity, elevated FBG, hypertension, hypertriglyceridemia, and low high-density lipoprotein (HDL) cholesterol, includes T2DM and forms the basis for pathologic processes such as atherosclerosis, which is characterized by enhanced recruitment of leukocytes to the endothelium. ⁵⁴ This syndrome is found in approximately half (47%) of women with PCOS. ⁵⁵ These agents were found capable of slowing rolling flux and adhesion of polymorphonuclear leukocytes, indicating overall slowed progression of atherosclerosis. ⁵⁶ Because of their metabolic derangements, such as MetS, women with PCOS were found to be at increased risk of atherosclerosis, which is why they may benefit from the cardiovascular protective properties of GLP-1RAs.^54,57

GLP-1RAs were also found to promote the production of nitric oxide, a critical molecule in the maintenance of vascular tone and endothelial function. ⁵⁴ Moreover, these agents exert an anti-inflammatory effect, where decreased macrophage infiltration, interleukin-1 beta (IL-1β), and IL-6 expression and an increase in IL-10 expression within the heart of a diabetic animal model were observed in one experiment. ⁵⁸

A study conducted on women with PCOS found higher levels of low-density lipoprotein (LDL) cholesterol, TGs, and lower levels of HDL cholesterol when compared to the control group. ⁵⁹ When treated with GLP-1RAs such as liraglutide, these women experienced a significant drop in BMI, which was linked to improvements in key cardiovascular risk factors, including BP, lipid profiles, and insulin sensitivity. ⁶⁰ Specifically, the study recorded a significant decrease in TC levels by 18.14 mg/dL, LDL cholesterol by 10.93 mg/dL, and TG by 49.1 mg/dL, along with a BMI reduction of −1.65 kg/m² (range: 0.72–2.58 kg/m²) after 3 months of treatment with this agent. ⁶⁰

Moreover, GLP-1RAs have demonstrated potential benefits in the regulation of BP, where a meta-analysis of liraglutide showed a mean systolic BP decrease of 2.5 mmHg within 2 weeks of treatment.^61,62 This may be beneficial for women with PCOS, who are 1.7 times more likely to develop hypertension than their counterparts. ⁶³ Also, GLP-1RAs were found to interact with the renin-angiotensin-aldosterone system (RAAS), a critical regulator of BP and fluid balance. ⁶¹ The intravenous infusion of GLP-1 in healthy subjects resulted in a decrease in the level of circulating Angiotensin II. ⁶¹ Additionally, one randomized control trial (RCT) found that liraglutide treatment in women with PCOS decreased levels of the cardiovascular risk biomarkers mid-regional pro-atrial natriuretic peptide (MR-proANP) by 25% and mid-regional pro-adrenomedullin (MR-proADM) by 6% when compared to placebo. ⁶⁴ MR-proANP can be used to assess the severity of acute and chronic heart failure, and MR-proADM was shown to be associated with mildly impaired diastolic left ventricular function, where mortality was observed to be higher in patients with elevated concentrations. ⁶⁵

Reproductive health benefits of GLP-1 RAs

PCOS is labeled a syndrome due to the various health problems that accompany it, notably infertility, where PCOS is considered to be the most common cause of the latter. ⁶⁶ The literature shows the importance of GLP-1RAs in treating PCOS in the metabolic and, even more so, in the reproductive aspect. ⁶⁶ Multiple studies demonstrate its role in the HPG axis, menstrual regularity, ovulation induction, ovarian morphology, and endometrial health, consequently improving fertility.^43,66–68

Effects on HPG and hypothalamic-pituitary-adrenal axis

In addition to their metabolic and cardiovascular effects, GLP-1RAs may influence the endocrine system, particularly the HPG axis. ⁶⁷ This axis, essential for regulating reproductive hormones and functions, may be affected by GLP-1RAs, potentially offering new therapeutic insights, especially for conditions like PCOS, where cardiovascular issues and hormonal imbalances are prevalent. ⁶⁷ GLP-1RAs enhance fertility by modulating hormonal imbalances: they can increase the LH surge by reducing hypothalamic-pituitary inhibition linked to estrogen excess in obesity (Figure 3(a)), or lower elevated LH levels associated with hyperinsulinemia. ²⁸ This is observed in a study, where an increase in the LH surge during the follicular phase was seen after the administration of GLP-1 centrally or peripherally in female rats, influencing estrogen and progesterone levels, which helped in the formation of more Graafian follicles and subsequently the corpus luteum, thus improving fertility ⁶⁹ (Figure 3(a)). Moreover, GLP-1RAs have been shown to increase LH release through GnRH stimulation, exerting a more prominent effect on the hypothalamus than on the pituitary. ⁶⁷ Notably, an elevated firing rate was observed in hypothalamic GnRH-Green Fluorescent Protein neurons of mice after GLP-1 receptor activation, alongside increased frequency of Gamma-Aminobutyric Acid-related miniature postsynaptic currents upon administration of Exendin-4, a GLP-1RA. ⁷⁰

Figure 3.

The reproductive impact of GLP-1RAs in PCOS. (a) The effect of GLP-1RAs on Fertility by modulating LH level. These agents can either increase LH levels by reducing the hypothalamic-pituitary inhibition linked to estrogen excess or lower the elevated LH levels due to over-aromatization of androgens to estrogen in the excess adipose tissue of women suffering from PCOS. This improves ovulation and corpus luteum formation.^28,68 (b) The significant improvement in the bleeding ratio among PCOS patients treated with Long-acting GLP-1RA, liraglutide, compared to placebo. ⁸¹ (c) The effect of GLP1-RA on the ovarian and endometrial tissues. The drug opposes the metabolic effect of PCOS, leading to a decrease in the toxicity of endometrial tissue and improvement of implantation. Additionally, it mitigates the effects of diabetes and hyperandrogenism on ovarian tissue by lowering the formation of cystic follicles.^43,82,86 (d) The beneficial effect of the combination of liraglutide and metformin, as well as metformin alone, on the improvement of IVF pregnancy and embryo transfer-related conception rates among PCOS patients, who are characterized by low conception rates due to excess weight.^20,88

Source: Generated with BioRender.

GLP-1RA, glucagon-like peptide-1 receptor agonists; IVF, in vitro fertilization; LH, luteinizing hormone; PCOS, polycystic ovary syndrome.

However, these stimulatory effects raise important considerations in the context of PCOS, a condition already marked by increased GnRH pulse frequency and elevated LH levels that drive hyperandrogenism and ovulatory dysfunction. ⁷¹ Since GLP-1RAs can further activate GnRH neurons and enhance LH secretion, they may theoretically aggravate this neuroendocrine imbalance. This paradox underscores the dual nature of GLP-1RAs in reproductive health, offering therapeutic promise while posing potential risks, particularly in hormonally sensitive conditions like PCOS. ⁷² While current clinical findings suggest an overall benefit, further studies are needed to clarify the central versus peripheral effects of these agents on the HPG axis.

In addition to modulating the HPG axis, GLP-1RAs may also impact the hypothalamic-pituitary-adrenal (HPA) axis, which plays a key role in androgen biosynthesis, particularly in PCOS. ⁷³ Dysregulation of the HPA axis is linked to altered cortisol production, which can increase adrenal androgen secretion. ⁷³ This occurs because chronic or altered adrenocorticotropic hormone (ACTH) stimulation of the adrenal cortex, the primary driver for cortisol, also stimulates the production of adrenal androgens like dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S), which share a common biosynthetic pathway. ⁷⁴ Given that GLP-1 receptors may influence cortisol secretion, GLP-1RAs could indirectly modulate androgen levels by altering adrenal function. ⁷³ The adrenal cortex has not been shown to express any GLP-1 receptors, and a study conducted on isolated adrenal cells from rats demonstrated no cortisol release in response to GLP-1 stimulation. ⁷⁵ This suggests that any effect on adrenal function is indirect and mediated through the central nervous system, where GLP-1RA in the hypothalamus influences ACTH release (Figure 2). ⁷⁶ However, the data are mixed. Recent studies have reported GLP-1 receptor expression in adrenal tissue in mice, predominantly in the adrenal cortex, with lower levels in the adrenal medulla.^77,78 Nevertheless, this short-term activation may not lead to long-term overstimulation of the HPA axis because, with chronic exposure, central GLP-1 receptors become desensitized, and the powerful negative feedback mechanisms of the HPA axis dominate, preventing a lasting rise in cortisol levels (Figure 2). ⁷⁹ Supporting this, one study found that long-term GLP-1RA (dulaglutide) exposure, when administered at the medically approved dosage, does not activate the HPA axis. ⁷⁹ This adds a layer of complexity to their effects on reproductive health, especially in conditions like PCOS, where both gonadal and adrenal androgen excess contribute to disease pathophysiology.

Figure 2.

The impact of GLP-1RA on the HPA axis: adrenal activation and androgen release. The indirect effect of GLP-1RA on the hormones released by the adrenal gland is mediated through central GLP-1 receptors. However, this effect is non-chronic due to receptor desensitization and the strong negative feedback mechanisms of the HPA axis.^76,79

Source: Generated with BioRender.

GLP-1RA, glucagon-like peptide-1 receptor agonists; HPA, hypothalamic-pituitary-adrenal axis.

These agents were also found to improve insulin sensitivity and weight control in women with PCOS, thereby reducing metabolic complications and hyperandrogenism. ³⁵ In a study done by Szczesnowicz et al., ¹⁶ a reduction of serum testosterone of about 0.29 nmol/L in 172 women treated for 3 months with GLP-1RA was seen.

Effect on menstruation and ovulation

These agents help restore a more regular hormonal pattern, supporting ovulation and a more consistent menstrual cycle. ⁸⁰ In a study done using exenatide alone or in combination with metformin, menstrual frequency and ovulation rates were shown to improve, along with weight reduction, which proves that losing weight has a major role in this effect. ⁶⁸ Moreover, GLP-1RA usage was associated with an improvement in natural pregnancy rate and menstrual regularity, where one investigation noted an increase in menstrual frequency (standard mean deviation: 1.72, 95% CI 0.60–2.85, p < 0.001, I² = 95.6%) and spontaneous pregnancy rates (risk ratio: 1.72, 95% CI 1.22–2.43, p = 0.002, I² = 0%) among 469 participants treated with these agents compared to 371 patients in the control group. ⁸⁰

In another study conducted on a group of women with prolonged irregular bleeding (>35 days), the bleeding ratio, which is the number of menstrual bleedings divided by the study period in months that can aid in the detection of menstrual irregularities and the impact of treatment, increased in 62% of patients suffering from PCOS in the liraglutide (1.8 mg/day) intervention group in comparison to placebo at 28% ⁸¹ (Figure 3(b)). Furthermore, their anti-inflammatory effects may contribute to a healthier hormonal environment, further improving menstrual regularity. ⁶⁹ With only one intracerebroventricular injection of GLP-1 during the follicular phase, the LH levels in this phase were increased, boosting the progesterone levels in the luteal phase of the estrous cycle in female rats, which increased the number of fetuses implanted and born. ⁶⁹

Effects on ovarian and endometrial morphology

The metabolic aspect of PCOS comprises dyslipidemia, IR, and T2DM, which together lead to the disruption of the ovaries. ⁶⁶ Research demonstrates the clinical benefits of GLP-1 and its agonists in fixing metabolic problems and positively affecting the ovarian function of PCOS patients. ⁶⁶ Studies in different settings, including in vitro, animal models, and human subjects, have been done to study the mechanisms of GLP-1RAs and their role in the ovaries. ⁸²

In the pathology of PCOS, the excess of androgens has been shown to play an important role in the early development of abnormal follicles. ⁸² The study conducted by Wu et al., ⁸² where the rats were manually injected with DHEA to induce PCOS, leading to the formation of small cystic follicles, showed that the administration of dulaglutide, which is a GLP-1RA, has a beneficial effect on both hormonal levels and ovarian morphology. This was observed through a decrease in the levels of the proteins that play a role in the synthesis of steroid hormones in the ovaries, such as the steroidogenic acute regulatory protein; a reduction in the number of preantral cystic follicles in the ovarian tissue; and an increase in the number of corpora lutea, when compared to placebo ⁸² (Figure 3(c)). Moreover, another study demonstrated similar results, where an increase in ovulation was seen after administering exenatide, leading to changes in the cellular levels in these follicles, such as the thickening of granulosa cell layers and the thinning of theca layer, which plays a role in the production of androgens. ⁸³

Regarding clinical trials and studies on human subjects, in a study by Nylander et al., ⁸¹ , the effects of liraglutide on the ovaries in PCOS were investigated. After 26 weeks of treatment, women in the intervention group experienced numerous beneficial changes compared to the placebo group, including weight reduction, improved bleeding ratio, decreased androgen levels, and reduced ovarian volume. ⁸¹ Metabolic disturbances, such as IR, that occur in patients with PCOS make the patient susceptible to glycemic regulation, ranging from impaired glucose tolerance to T2DM. ⁸⁴ Interestingly, T2DM and IR are found to have a toxic effect on ovaries, leading to the degeneration of the gonadal tissue and the reduction in the ovarian reserve. ⁸⁵ However, giving GLP-1RAs improved the former’s histology by reducing its degeneration, fibrosis, and oxidative stress ⁴³ (Figure 3(c)).

Concerning the effect of PCOS on the endometrium, its metabolic factors play a significant role in inducing toxicity and increasing cellular metabolism in the upper layer, which adds an obstacle to proper implantation and placental formation^43,86 (Figure 3(c)). Notably, exenatide showed a positive effect in rats by reversing these effects and improving conception.^43,85 However, further clinical studies are needed to establish the efficacy in the human model. ⁴³

Effects on fertility and in vitro fertilization

The majority of anovulatory infertility cases among women of childbearing age are caused by PCOS. ⁸⁷ Obesity is thought to exert an effect on the HPG axis through the role of excess fat in the aromatization of androgen to estrogen; consequently, the latter induces negative feedback on the HPG axis, leading to sub-fecundity and infertility. ²⁰ In addition to the other mechanisms, such as IR and high androgen levels, that lower fertility by affecting the ovaries and endometrium. ²⁰ The research emphasized the correlation between infertility and the degree of obesity, concluding that weight reduction in PCOS aids in improving fertility. ²⁰ Thus, GLP-1RAs show an improvement in overall fertility on the scale of ovulatory rates, menstrual cycles, pregnancy rates, and bleeding ratio. ⁵¹ Altogether, this adds to the beneficial profile of GLP-1RAs in PCOS, specifically the reproductive aspect. ⁵¹ In a study, exenatide was compared to metformin in obese PCOS patients, where exenatide or metformin was administered for the first 12 weeks, followed by metformin alone for the subsequent 12 weeks. ⁵¹ It was found that the natural pregnancy rate showed higher values at 43.6% in the exenatide-treated groups at a dosage of 10 μg twice daily versus the other group at 18.7%. ⁵¹

When it comes to in vitro fertilization (IVF) in PCOS patients, excess weight plays a major role in reducing conception rates, where it hinders IVF procedures by reducing the number and the quality of retrieved mature follicles and oocytes, increasing the cycle termination rate ²⁰ (Figure 3(d)). Moreover, PCOS patients undergoing assisted reproductive techniques to conceive a child usually have an expected pregnancy rate value of 30%. ⁸⁸ In an RCT that spanned over 12 weeks of treatment, natural and IVF-induced conception rates were assessed after administering liraglutide at a low dose (1.2 mg once a day), combined with metformin for the first group and only metformin for the other. ⁸⁸ The pregnancy rate per embryo transfer rose to 85.7%, and the overall pregnancy rate reached 69% in the combination group, while it reached values of 28.6% and 35.7%, respectively, in the metformin group ⁸⁸ (Figure 3(d)). This implies that the pregnancy rate post-IVF in PCOS patients under metformin therapy or with no treatment is similar at about 30%, but the addition of liraglutide significantly increased the rates to 85%. ⁸⁸ It is important to note that both groups were resistant to other reproductive treatments, and weight loss was observed in both groups, indicating the potential existence of other mechanisms exerted by GLP-1RAs that improve pregnancy outcomes other than weight loss.^27,88

GLP-1RAs constitute a promising option among the treatment pool for patients suffering from PCOS and seeking help in improving their reproductive function. ¹⁶ This is especially seen in assisted reproductive settings used due to infertility problems stemming from advanced age and poor ovarian reserve, where it can play a role in mitigating metabolic and reproductive disturbances and enhancing the odds of pregnancy post-IVF. ¹⁶ It is known that with advancing age, women experience a decline in their ovarian reserve and subsequent fertility. ⁸⁹ In contrast, studies found that, among PCOS patients, the levels of AMH and antral follicular count decline much more slowly when compared to their healthy counterparts.^90,91 However, it does not translate into better fertility outcomes due to the presence of several other factors, such as IR, that affect the ovaries and the reproductive function. ⁹² Nevertheless, such outcomes suggest a higher chance of improved fecundity rates following IVF treatment at more advanced ages, such as 40 years, due to the presence of these hormones when compared to non-PCOS patients. ⁸⁹ This highlights the importance of addressing existing metabolic issues and initiating early IVF treatment to achieve successful outcomes. ⁸⁹

Once again, studies confirm the efficacy of GLP-1RAs in addressing reproductive problems in women with PCOS; however, it is essential to point out a significant finding in this study. ⁹³ Based on mouse models, where the glucagon gene was disrupted by the insertion of green fluorescent protein, abolishing the synthesis of its products, including GLP-1. ⁹³ The authors found that reproductive functions, such as litter size, bleeding ratios, and pregnancy rates, were reduced in the knocked-out group in comparison to the other group. ⁹³ This indicates that these peptides are not crucial for conception, but may play a role that needs investigation to specify. ⁹³

Long-term reproductive health concerns

There are numerous benefits conferred by administering GLP-1RAs to women suffering from PCOS. ¹⁶ GLP-1RAs are considered to have a good safety profile. ²⁷ However, considerations should be taken for the drug safety profile; for example, caution must be taken in the case of a patient suffering from gastroparesis since the activation of the GLP-1 receptor through the administration of an agonist leads to a decrease in gastric emptying, which induces an exacerbation of symptoms and even the discovery of the disease after drug intake. ⁹⁴ Also, ruling out existing contraindications like diabetic retinopathy and medullary thyroid cancer is necessary. ¹⁶ Regarding the risk of pancreatitis, it was shown in this study that 70.2% of cases of hypoglycemic agents-induced pancreatitis were related to GLP-1RA after analysis of reports of 2313 patients. ⁹⁵ Moreover, its co-administration with RAAS inhibitors needs to be cautious to avoid the heightened risk of dehydration and volume contraction. ¹⁶ Fortunately, considering that these issues are easily avoided, PCOS patients generally tolerate incretin mimetics, knowing the ultimate goal is to have intact pregnancies.^27,43

Notably, these drugs are used during the preconception period, where promising results are observed in both natural and IVF pregnancy rates after administration. ⁴⁷ However, it is not advised during pregnancy as it is considered a class C drug, defined as a drug with established risk that cannot be ruled out.^16,47,96 Studies on animals indicate possible fetal damage, including death and birth abnormalities, as well as prospective problems, including growth restriction and preterm birth; however, human studies have not revealed significant abnormalities with first-trimester exposure.^97,98 In this prospective observational cohort study published in 2024, which spanned a timeline between 2009 and 2022, the risk of teratology was assessed. ⁹⁷ Compared to other reference groups receiving non-GLP-1RAs drugs or no treatment, a study including 168 women, who took any one of the GLP-1RAs throughout the first trimester for diabetes or obesity-related illnesses, revealed no increased risk of birth abnormalities or congenital malformations, scoring a value of 2.3%, which aligns with the European Surveillance of Congenital Anomalies value of 2.6%.^97,99 Consequently, this study reassures the usage safety of both short-acting and long-acting GLP-1RAs during the first trimester of pregnancy. ⁹⁷ Additionally, another study that established the risk of major congenital malformations after preconception intake of either insulin or other antidiabetic medications, including GLP-1RAs, found no increase above the established risk in the case of women with pre-gestational diabetes when compared to insulin. ¹⁰⁰

Regarding contraception during GLP-1RAs therapy, OCPs stand as the most common way used among women of childbearing age. In a review of clinical trials, the combination of combined oral contraceptive pills (COCPs) with either a GLP-1RA or tirzepatide (GLP-1 and Glucose-dependent insulinotropic polypeptide (GIP) receptors agonist) did not affect the efficacy of contraceptive drugs, even though GLP-1RAs can decrease the absorption of the concomitantly administered drug through their gastric delaying effect. ¹⁰¹ Therefore, it can be advised to administer OCPs 1 h post-hypoglycemic drug treatment. ¹⁰¹

Moreover, due to their long half-life, a washout period of at least 2 months should be taken before trying to conceive, which is stated in the semaglutide approval package inserts. ⁴⁷ Consequently, to achieve the expected goals and efficacy, GLP-1RAs require vigilant monitoring, which is accomplished through patient awareness and willingness to take the treatment. ¹⁶

However, the question remains as to how metabolic and reproductive therapies can be balanced when the goal of using GLP-1RAs in PCOS patients is to improve reproductive functions, primarily by targeting and modifying the disease’s metabolic features. ²⁷ Achieving this goal requires a clear characterization of the study population, detailed clinical assessment, regular monitoring, disease sub-phenotyping, and consideration of patient conditions, eating behaviors, metabolic abnormalities, and psychosocial factors. ²⁷ In addition, the current RCTs differ in numerous characteristics, for example, dosage values, follow-up duration, type of incretin mimetics, and population characteristics, such as BMI, laboratory tests, and more. ²⁷ This emphasizes the need for robust and well-designed RCTs with a large population and longer duration to establish the extent of the role of GLP-1RAs in different subpopulations. ²⁷

Drug-drug interactions with GLP-1RAs in PCOS

Comparison with metformin

Metformin is an antidiabetic that has been on the market for more than 50 years before GLP-1RA.^17,102 It works by decreasing hepatic glucose production, thereby lowering blood glucose in diabetic patients. ¹⁷ In addition, it helps reduce insulin levels and improve androgen levels in PCOS patients. ¹⁷ However, compared to GLP-1RA, metformin does not affect the beta-cell function, which is the primary pathophysiological problem in T2D diabetic patients. ¹⁰³

The comparison between the effects of combined metformin and GLP-1RAs has attracted the attention of researchers. ¹⁰⁴ Multiple studies target the effects of both drugs in managing the metabolic and reproductive health of women with PCOS. ¹⁰⁴ A thorough investigation of the existing literature revealed a range of conflicting perspectives regarding the best method to administer these two drugs, whether combined or as monotherapy. ¹⁰⁴

Studies, such as the one conducted by Ma et al., ¹⁰⁴ suggested no significant difference between GLP-1RAs and metformin therapies and between combination therapy and GLP-1RAs alone. However, the results of a meta-analysis showed that GLP-1RAs can reduce BMI and WC more effectively than metformin. ¹⁰⁵ These results were supported by Srinivasan et al., ¹⁰⁶ showing in their study an improvement in weight and insulin sensitivity, where using GLP-1RAs in monotherapy versus metformin achieved more than 5% weight loss. Nevertheless, no significant difference was detected regarding metabolic indices, such as Diastolic BP, systolic BP, TC, and TG. ¹⁰⁵

Concerning the effect of these drugs on reproductive function, no significant difference was determined between GLP-1RAs and metformin for improving menstrual rate, decreasing serum testosterone, and free androgen index (FAI). ¹⁰⁵ However, according to some references, GLP-1RAs showed an improvement in reproductive function by reducing abdominal adiposity, which is responsible for endocrine and reproductive dysfunctions in women with PCOS.^51,88 Accordingly, two studies (Liu et al. ⁵¹ and Salamun et al. ⁸⁸ ) stated that GLP-1RAs had beneficial effects on reproductive function in patients with PCOS.

However, comparing metformin and GLP-1RAs shouldn’t be solely limited to their effects; comparing their safety is also a key measure to choosing which one is feasible to recommend. ¹⁰⁴ The most common side effect for both GLP-1RAs and metformin is moderate gastrointestinal discomfort, which can be soothed by gradual dose titration, eating small portions meals but with a higher frequency, and avoiding some compounds, including stimulant or secretory substances (caffeinated beverages, spices) and those known to cause relaxation of lower esophageal sphincter (fatty, fried or processed foods, chocolate, tomato, mint).^104,107 Other references considered that GLP-1RAs were more likely to cause nausea and headache than metformin. ¹⁰⁵

Comparison with other pharmacological agents

Researchers were interested in comparing the benefits of using various drugs in treating PCOS. ¹⁰⁸ In terms of anthropometric effects, Goldberg et al. ¹⁰⁹ stated that within 12 weeks, GLP-1RAs (exenatide, liraglutide, and semaglutide) have a weight reduction efficacy corresponding to metabolic and reproductive benefits in women with PCOS. However, the greatest weight loss and abdominal fat reduction, which was measured by dual X-ray absorptiometry, were seen in GLP-1RAs combined with sodium-glucose cotransporter-2 inhibitors (SGLT2i) and phentermine topiramate. ¹⁰⁸

COCPs can be beneficial in PCOS patients, especially those who do not intend to become pregnant. ¹¹⁰ This is primarily due to their positive effects on controlling the menstrual cycle, lowering testosterone levels, and preventing endometrial hyperplasia. ¹¹⁰ However, their impact on metabolic health remains a concern. ¹¹¹ Although COCPs have been shown to alter metabolic parameters, there is ongoing research that continues to debate their impact on weight status. ¹¹¹ While most studies have reported weight gain associated with their use,^112–114 only a few reveal increasing anthropometric parameters without significant modifications in total body weight. ¹¹¹ Additionally, orlistat was shown to be superior to COCPs in terms of anthropometric outcomes, but not in metabolic outcomes ¹⁰⁹ (Table 1).

Table 1.

Comparative efficacy of pharmacological agents in PCOS management.^{51,68,88,108,109,116,117}

Pharmacological interventions	Weight reduction	Metabolic benefit a	Hormonal regulation	Reproductive benefit b	Adverse drug reaction
Combined therapy	+++ GLP-1RAs/SGLT2i or topiramate	+++ Metformin/GLP-1RAs or TZDs	+++ GLP-1RAs/Metformin	+++ Metformin/GLP-1RAs or TZDs	+
GLP-1RAs	++	++	++	+ c	+
Metformin			++		+
SGLT2i	++				+
Topiramate	++				+
Orlistat	++				+
COCP	−				+
TZDs	−		++		+

The table uses “+++” for high efficacy, “++” for moderate efficacy, “+” for mild efficacy, and “−” for weight gain or no efficacy. The symbol “/” indicates “with.” Cells remaining empty mean a lack of data.

^aLDL-C and FBG.

^bMenstrual recovery and pregnancy rate.

^cNo increased pregnancy loss risk; https://pubmed.ncbi.nlm.nih.gov/38663923/.

COCP, combined oral contraceptive pills; FBG, fasting blood glucose; GLP-1RAs, glucagon-like peptide-1 receptor agonists; LDL-C, low-density lipoprotein cholesterol; PCOS, polycystic ovary syndrome; SGLT2i, sodium-glucose cotransporter-2 inhibitors; TZDs, thiazolidinediones.

Regarding TZDs (glitazones), a family of drugs consisting of only two FDA-approved drugs to manage T2DM: pioglitazone and rosiglitazone. ¹⁹ These drugs are sometimes used off-label to treat PCOS, through promoting insulin sensitivity and improving the reproductive function.^19,103 However, a prominent adverse effect of TZDs is weight gain, thought to be primarily caused by a rise in body fat and retention of fluids. Visceral fat is either reduced or has minimal effect on fat gain, mainly occurring in subcutaneous adipose tissue. ¹¹⁵ Additionally, TZDs have been shown to be the least effective in diminishing BMI. ¹¹⁶

Regarding hormonal regulation, according to Yang et al., ¹¹⁷ metformin helped reduce total serum testosterone, while the combined therapy of GLP-1RAs and metformin was more effective in decreasing FAI. TZDs had a greater effect on SHBG than metformin. ¹¹⁷ Therefore, the combined therapy of GLP-1RAs and metformin is the recommended choice for cases of hyperandrogenism. ¹¹⁷ This combined therapy was also shown to be associated with higher SHBG, lower FT, androstenedione, and lower FBG. ¹¹⁶ Other studies stated that reductions in FBG, testosterone, FAI, and BP were seen with all drugs, and the use of dual therapy of GLP-1RA/SGLT2i (exenatide/dapagliflozin) was superior to either alone, dapagliflozin/metformin and phentermine topiramate, in terms of clinical and metabolic benefits in this patient population. ¹⁰⁸ It should be noted that TZDs are the least effective of all oral anti-diabetic drugs in reducing androstenedione. ¹¹⁷ Xing et al. ¹¹⁶ demonstrated that the use of dual therapy of metformin, whether with GLP-1RAs or TZDs, was superior to monotherapy in improving hyperandrogenemia in women with PCOS. Even though limited, it is worth mentioning that one trial suggested an increased pregnancy rate with pre-gestational exenatide compared with metformin; nevertheless, there was no significant difference between groups for live birth rate. ¹⁰⁹ In addition, GLP-1RAs have the same efficacy as TZDs when combined with metformin for menstrual recovery ¹¹⁷ (Table 1).

Overview of clinical trials on GLP-1RAs for PCOS

Human clinical trials

Trial characteristics

In November 2024, we conducted a systematic search on ClinicalTrials.gov for interventional clinical trials related to GLP-1RAs and PCOS. The characteristics of each trial were collected. Linked publications were searched using Medline/PubMed and Embase/Scopus, and the content of trials was reviewed and summarized in Tables 2 and 3.

Table 2.

Published clinical trials on GLP1 and PCOS found on ClinicalTrials.gov as of November 2024 (n = 13).

NCT number	Study title	Conditions	Study status	Interventions	Phase	Enrollment	Start date	Location	DOI
NCT03151005	The effect of GLP-1 agonists versus OCs on reproductive disorders and cardiovascular risks in overweight PCOS	PCOS, obesity	Completed	DRUG: metformin-GLP-1RAs, DRUG: metformin-OC	IV	70	7/1/2017	China	https://doi.org/10.1007/s12020-023-03487-4
NCT04876027	GLP-1 RAs in patients with polycystic ovary syndrome (PCOS)	PCOS	Completed	DRUG: GLP-1RAs, OTHER: calorie restricted diet	IV	68	2021/05/15	China	N/A
NCT04029272	Metformin vs metformin combined with GLP-1RA (GLP-1RA) on overweight/obese PCOS patients	PCOS	Unknown	DRUG: Metformin, DRUG: Exenatide 2 MG	IV	80	2019/07/20	China	https://doi.org/10.1097/cm9.0000000000001712
NCT01899430	Polycystic ovary syndrome and liraglutide	PCOS, obesity	Completed	DRUG: LIRA, DRUG: metformin	IV	32	2011/11	Slovenia	N/A
NCT02187250	PDE-4 inhibitor roflumilast and GLP-1 agonist liraglutide in polycystic ovary syndrome	PCOS, obesity	Completed	DRUG: metformin, DRUG: LIRA, DRUG: roflumilast	IV	45	2014/03	Slovenia	https://doi.org/10.1186/s13048-015-0161-3
NCT02635386	EQW, DAPA, EQW/DAPA, DAPA/MET ER and PHEN/TPM ER in obese women with polycystic ovary syndrome (PCOS)	PCOS, obesity	Completed	DRUG: EQW, DRUG: DAPA, DRUG: EQW plus DAPA, DRUG: DAPA plus Glucophage, DRUG: PHEN/TPM ER	III	119	22/6/2016	United States	https://doi.org/10.1210/clinem/dgab408
NCT01911468	Polycystic ovary syndrome and liraglutide as add-on therapy on metformin	PCOS, obesity	Completed	DRUG: metformin, DRUG: LIRA, DRUG: metformin and LIRA	IV	36	2011/11	Slovenia	https://doi.org/10.3109/07435800.2014.966385
NCT03480022	Liraglutide 3 mg (Saxenda) on weight, body composition, hormonal, and metabolic parameters in obese women with PCOS	PCOS, obesity	Completed	DRUG: Saxenda, DRUG: placebo LIRA pen injector	III	88	26/9/2018	United States	https://doi.org/10.1016/j.fertnstert.2022.04.027
NCT05965908	Effect of liraglutide in obese women with polycystic ovary syndrome	PCOS	Not yet recruiting	DRUG: LIRA, DRUG: metformin	III	120	2023/07/30	Egypt	N/A
NCT0952882	Liraglutide and metformin combination on weight loss, metabolic-endocrine parameters and pregnancy rate in women with PCOS, obesity and infertility	PCOS, obesity, infertility	Not yet recruiting	DRUG: LIRA + metformin, DRUG: metformin	III	188	2023/11/01	Vietnam	N/A
NCT00344851	Exenatide and metformin therapy in overweight women with PCOS	PCOS	Completed	DRUG: metformin, exenatide, or combined	II	60	2006/06	United States	https://doi.org/10.1210/jc.2008-0115
NCT02909933	Low dose liraglutide and metformin vs high dose liraglutide alone in treatment of obesity	PCOS, obesity	Completed	DRUG: LIRA, DRUG: metformin and LIRA	IV	30	2015/07	Slovenia	https://doi.org/10.1186/s12902-017-0155-9
NCT02073929	LIPT—liraglutide in polycystic ovary syndrome	PCOS	Completed	DRUG: LIRA for 26 weeks, DRUG: placebo	IV	72	2014/03	Denmark	https://doi.org/10.1111/dom.13053

DAPA, dapagliflozin; DE-4, phosphodiesterase-4; DOI, digital object identifier; EQW, exenatide once weekly; GLP-1RAs, glucagon-like peptide-1 receptor agonists; Glucophage, metformin extended-release; LIPT, liraglutide in polycystic ovary syndrome trial; LIRA, liraglutide; MET ER, metformin extended release; N/A, not available; OC, oral contraceptive; PCOS, polycystic ovary syndrome; PHEN/TPM ER, phentermine/topiramate extended release; Saxenda, brand name for liraglutide pen injector.

Table 3.

Clinical trial summary on PCOS treatments: Efficacy and outcomes.

NCT number	Study design	Aim	Conclusion/results
NCT03151005	Allocation: Randomized Intervention model: Parallel Masking: Triple (participant, investigator, outcomes_assessor) Primary purpose: Treatment	Compare metformin-GLP-1RA vs metformin-Diane-35 on lipid metabolism and cardiovascular risks in overweight PCOS.	GLP-1RA + metformin was superior in improving body composition, metabolic health, and ovulation compared to CPA/EE + Met, with novel biomarkers suggesting targets for PCOS.
NCT04876027	Allocation: Randomized Intervention model: Parallel Masking: None Primary purpose: Treatment	Assess whether GLP-1RA with calorie restriction reduces more visceral fat in overweight/obese PCOS patients at 7% weight loss vs diet alone.	Data not available.
NCT04029272	Allocation: Randomized Intervention model: Parallel Masking: None Primary purpose: Treatment	Test if metformin plus exenatide is more effective than metformin alone in overweight/obese PCOS women.	Exenatide combined with metformin improved weight, insulin sensitivity, and metabolic markers, offering a tolerable and effective treatment for PCOS.
NCT01899430	Allocation: Randomized Intervention model: Parallel Masking: None Primary purpose: Treatment	Compare LIRA vs metformin in obese women with newly diagnosed PCOS.	LIRA significantly reduced weight and improved eating behaviors in obese women with PCOS.
NCT02187250	Allocation: Randomized Intervention model: Parallel Masking: None Primary purpose: Treatment	Evaluate the effectiveness of PDE-4 inhibitor roflumilast vs GLP-1RA LIRA or metformin in treating obese PCOS women.	LIRA outperformed metformin in weight management and glucose control, with modest benefits from roflumilast suggesting potential alternative treatments.
NCT02635386	Allocation: Randomized Intervention model: Parallel Masking: Single (investigator) Primary purpose: Treatment	Compare five treatments (EQW, DAPA, EQW + DAPA, DAPA/metformin, PHEN/TPM) on metabolic, endocrinological, and reproductive outcomes in overweight/obese, non-diabetic women with PCOS.	Exenatide and dapagliflozin combination showed superior results in weight reduction, insulin sensitivity, and body composition in obese women with PCOS.
NCT01911468	Allocation: Randomized Intervention model: Parallel Masking: None Primary purpose: Treatment	Assess if LIRA + metformin is more effective than monotherapies in previously poor responders with obese PCOS.	LIRA significantly improved weight and eating behavior in obese women with PCOS.
NCT03480022	Allocation: Randomized Intervention model: Parallel Masking: Quadruple (participant, care provider, investigator, outcomes_assessor) Primary purpose: Treatment	Investigate the best treatment for weight reduction and metabolic improvement in obese, non-diabetic women with PCOS using LIRA and anti-obesity drugs.	LIRA 3 mg was superior to placebo in reducing weight, improving insulin sensitivity, and addressing hyperandrogenism with favorable reproductive outcomes in PCOS.
NCT05965908	Allocation: Randomized Intervention model: Parallel Masking: None Primary purpose: Treatment	Compare hormonal, metabolic, and clinical effects of metformin vs LIRA in infertile women with PCOS.	Data not available.
NCT05952882	Allocation: Randomized Intervention model: Parallel Masking: None Primary purpose: Treatment	Evaluate anti-obesity drugs combined with lifestyle changes on weight, metabolic function, and pregnancy outcomes in obese PCOS women.	Data not available.
NCT00344851	Allocation: Randomized Intervention model: Parallel Masking: None Primary purpose: Treatment	Compare exenatide, metformin, and combination therapy on menstrual cyclicity, hormone, and metabolic profiles in PCOS women.	Exenatide and metformin combination was most effective in improving menstrual cycles and ovulation, linked to weight loss and improved metabolic parameters.
NCT02073929	Allocation: Randomized Intervention model: Parallel Masking: Quadruple (participant, care_provider, investigator, outcomes_assessor) Primary purpose: Treatment	Investigate the effects of GLP-1RAs on cardiovascular disease risk markers in PCOS.	LIRA reduced liver fat, visceral adipose tissue, and cardiovascular biomarkers in PCOS women, suggesting broader health benefits.
NCT02909933	Allocation: Randomized Intervention model: Parallel Masking: None Primary purpose: Treatment	Test short-term LIRA combined with metformin vs high-dose LIRA alone for weight loss in obese PCOS women.	LIRA significantly reduced body weight, liver fat, and visceral adipose tissue, with improvements in hormonal and metabolic health in obese women with PCOS.

CPA/EE, cyproterone acetate/ethinylestradiol; DAPA, dapagliflozin; Diane, a brand name for a COCP; DXA, dual-energy X-ray absorptiometry; EQW, exenatide once weekly; FAI, free androgen index; GLP-1RA, glucagon-like peptide-1 receptor agonists; HOMA-IR, homeostasis model assessment of insulin resistance; IGI/HOMA, insulinogenic index divided by HOMA; LIRA, liraglutide; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; PDE-4, phosphodiesterase-4; PHEN/TPM, phentermine/topiramate; Roflumilast, a selective PDE-4 inhibitor.

There are currently 13 clinical trials investigating GLP-1RAs for PCOS registered with a National Clinical Trial number, targeting various outcomes of GLP-1RAs on PCOS patients, including weight loss, hormonal changes, metabolic health, and reproductive parameters. Across all studies, approximately 1066 participants are involved, with enrollment ranging from smaller pilot studies involving 30–70 participants to larger trials enrolling over 100 participants, with some phase III trials reaching as high as 188 participants. Variability in enrollment might reflect local recruitment challenges or specific inclusion criteria, such as obesity or infertility in PCOS patients (Table 2). These trials span different phases, including several phase III studies (n = 4) primarily in the U.S. and China, focusing on efficacy and safety in larger populations, and only one clinical trial in phase II, indicating that they are either testing effectiveness on a larger scale or assessing long-term effects post-market release. Most studies investigating combination treatments (e.g., GLP-1RAs with metformin) are in phase IV (n = 8), assessing long-term effects and comparative efficacy in real-world settings. These studies span multiple countries, primarily China, Slovenia, and the United States, with dates ranging from 2006 to recent years. This geographic diversity helps capture data across populations with varying genetic and lifestyle backgrounds, providing insights into how PCOS treatments perform under different conditions (Table 2). Interventions primarily include drugs like metformin and GLP-1RAs (e.g., liraglutide), with some combining drugs for enhanced effectiveness. These combinations aim to tackle the metabolic and endocrine disruptions seen in PCOS, such as IR, weight gain, and irregular cycles. Drugs like exenatide, dapagliflozin, and phentermine/topiramate are tested for their weight loss and insulin-sensitizing effects. Calorie restriction alongside pharmacotherapy is also assessed, which highlights lifestyle modification’s role in treatment (Table 2).

Trials-focused results and summary of outcomes

Body composition

GLP-1RAs have consistently shown positive effects on body composition in women with PCOS in many RCTs. In the RCT by Liao et al., ¹¹⁸ the GLP-1RA (liraglutide) with metformin group (n = 30 cases) demonstrated significantly greater reductions in weight, BMI, and WC compared to the (n = 30 cases) CPA/ethinylestradiol (EE) with metformin group. After 12 weeks of treatment, the GLP-1RA/metformin group experienced average decreases of 7.40 kg in weight, 2.90 kg/m² in BMI, and 7.22 cm in WC, whereas the CPA/EE/metformin group showed more modest reductions of 1.85 kg, 0.76 kg/m², and 2.53 cm, respectively. ¹¹⁸ These differences were statistically significant, with p-values <0.001 for weight and BMI and a p-value equal to 0.001 for WC, highlighting the superior efficacy of the GLP-1RA/metformin regimen in addressing obesity-related parameters in overweight women with PCOS. ¹¹⁸ Additionally, Ma et al. ¹¹⁹ demonstrated that exenatide combined with metformin (n = 19 patients) led to more pronounced reductions in body weight (mean reduction of 4.5 kg) and WC (by 4 cm) compared to metformin alone (n = 21 patients). Jensterle et al. ¹²⁰ reported that liraglutide treatment (n = 14 patients) resulted in a significant 3 kg weight reduction, significantly outperforming metformin (n = 13) in weight management. Moreover, Elkind-Hirsch et al. ³⁴ found that liraglutide (n = 55) significantly decreased fat mass and waist-to-hip ratio (WHR), with reductions of 3.1 kg in fat mass and 0.08 in WHR. Also, Frøssing et al. ⁵² showed that liraglutide led to a 5.6% reduction in body weight (5.2 kg) and a 44% reduction in liver fat content, underscoring the compound’s efficacy in managing central adiposity and fat distribution in PCOS (n = 72 women with PCOS; Table 3).

Metabolic health

Metabolic improvements were evident in multiple studies investigating GLP-1RAs. Liao et al. ¹¹⁸ showed that GLP-1RAs with metformin improved glucose metabolism and IR, evidenced by reductions in HbA1c (by 0.9%), FBG (by 12 mg/dL), and HOMA-IR decreased by 0.6). Ma et al. ¹¹⁹ demonstrated that combined exenatide and metformin enhanced insulin sensitivity, although improvements in HOMA-IR were not statistically significant. However, Jensterle et al. ¹²⁰ reported that liraglutide outperformed metformin in improving glucose control, reducing HbA1c by 0.5%. Lastly, Frøssing et al. found that liraglutide treatment led to reductions in FBG and leptin, improving IR and demonstrating favorable metabolic effects in women with PCOS ⁵² (Table 3).

Reproductive function

GLP-1RAs have also been associated with improvements in the reproductive function of women with PCOS. Liao et al. ¹¹⁸ found improvements in the menstrual cycles and follicle formation in both treatment groups, but GLP-1RAs with metformin were more effective in improving ovulation rates (58% of patients ovulated) compared to CPA/EE with metformin (44%). The trials of both Ma et al. ¹¹⁹ and Jensterle et al. ¹²⁰ showed that treatment with GLP-1RAs resulted in reduced testosterone levels, which improves hyperandrogenic symptoms and enhances menstrual regularity. Elkind-Hirsch et al. ⁶⁸ demonstrated that exenatide combined with metformin resulted in an 86% ovulation rate, significantly higher than the 50% ovulation rate in the exenatide-only group and 29% in the metformin-only group. Elkind-Hirsch et al. ³⁴ also showed in another trial that liraglutide treatment improved menstrual cyclicity in 60% of women, and two women achieved pregnancy during the study period, further supporting GLP-1RAs’ role in improving fertility outcomes (Table 3).

Inflammatory and oxidative markers

GLP-1RAs have been shown to positively influence inflammatory and oxidative stress markers in women with PCOS. Liao et al. ¹¹⁸ reported that GLP-1RAs with metformin improved oxidative stress markers, such as IL-6, suggesting a reduction in systemic inflammation. This was supported by protein changes indicating enhanced immune modulation and cellular detoxification. In contrast, Ma et al. ¹¹⁹ and Jensterle et al. ¹²⁰ did not report significant findings related to inflammatory markers. Elkind-Hirsch et al. ¹⁰⁸ indicated that the combination of exenatide and dapagliflozin decreased inflammatory markers linked to obesity, such as C-reactive protein and TNF-α. Although his new trial on liraglutide a year later did not provide specific inflammatory data after 32 weeks of the trial duration, the significant reductions in central adiposity and fat mass likely contributed to lowered systemic inflammation ³⁴ (Table 3).

Proteomic analysis

Proteomic analysis revealed further insights into the mechanisms underlying the metabolic and reproductive benefits of GLP-1RAs. Liao et al. ¹¹⁸ identified key proteins related to oxidative stress and immune modulation, including a decrease in markers such as Peroxiredoxin 6 (PRDX6) and Fibronectin 1 (FN1), which are linked to ROS detoxification and immune response. These changes suggest that GLP-1RAs with metformin may enhance cellular resilience to oxidative damage. ³⁴ However, Elkind-Hirsch et al. ³⁴ revealed that the exenatide/dapagliflozin combination therapy impacted proteins involved in fat metabolism and insulin sensitivity, further supporting the therapeutic potential of these combinations. While other trials did not include proteomic analysis, the findings of metabolic improvements and weight loss indirectly suggest alterations in key metabolic proteins^34,52 (Table 3).

Animal clinical trial results

GLP-1RAs, particularly liraglutide and semaglutide, have shown promising results in managing metabolic disturbances in PCOS animal models. In a hyperandrogenic rat model of PCOS, liraglutide significantly reduced body weight from 294.75 ± 3.2 to 276.25 ± 2.7 g (p < 0.01), decreased abdominal adiposity, and lowered TC levels to match controls. ¹²¹ Additionally, liraglutide improved glucose tolerance, reduced post-OGTT levels to control levels, and lowered both systolic and mean arterial BP (p < 0.05). ¹²¹ These effects were similarly noted in dihydrotestosterone (DHT)-induced PCOS mice, where liraglutide reduced body weight, enhanced glucose tolerance, and corrected the estrous cycle. ¹²¹ In another study, semaglutide was tested in mice subcutaneously injected with DHEA for 21 days to establish the PCOS model, and showed even more significant effects, including reduced body weight, improved glucose tolerance, as indicated by reduced FBG and reduced Intraperitoneal Glucose Tolerance Test, and a reduction in ovarian cystic follicles, with an increase in the corpus luteum. ³⁷

In murine models treated with GLP-1-based multi-agonists, such as GLP-1RAs/estrogen and triagonist (combining GLP-1, GIP, and glucagon), substantial improvements in metabolic function were observed, including significant reductions in body weight, fat mass, and circulating leptin levels. ¹²² Two PCOS mouse models were developed using prenatal androgenization (via DHT administration to pregnant dams on gestational days 16–18) and postweaning androgenization (via subcutaneous DHT implants at day 21), followed by high-fat diet exposure and 28-day treatment with GLP-1-based mono- and multi-agonists or metformin starting on postnatal day 80, with outcomes assessed at day 108. ¹²² The triagonist synergistically enhances metabolic benefits by promoting glucose-dependent insulin secretion, improving fat oxidation, and increasing energy expenditure. ¹²² Treatments with the triagonist significantly reduced body weight, fat mass, and circulating leptin levels. ¹²² While the triagonist reduced ovarian weight and LH levels in one model, it did not restore ovarian cyclicity or histological markers of ovarian function in either PCOS model. ¹²² Interestingly, GLP-1/estrogen demonstrates a promising role in improving ovarian cyclicity in milder PCOS phenotypes with preserved ovulatory function, effectively normalizing cycle irregularities and enhancing reproductive hormonal balance, while, at lower doses, it outperformed other multi-agonists by reducing body weight (by 10%), fat mass (by 50%), and improving glucose metabolism and insulin sensitivity in PCOS models, without causing significant changes in ovarian or uterine parameters. ¹²²

Lastly, liraglutide’s impact on food intake and body weight in postmenopausal PCOS rats showed initial reductions in food intake, though this effect diminished over time (tachyphylaxis), with a consistent reduction in body weight and abdominal fat, along with a decrease in BMI and fat mass in PCOS rats more than in controls. ¹²³ These findings support the potential of GLP-1RAs, particularly liraglutide and semaglutide, as effective treatments for managing both metabolic and cardiovascular symptoms in PCOS.

Conclusion

This review highlights that GLP-1RAs provide a multifaceted approach to managing PCOS, offering substantial benefits across both metabolic and reproductive domains. The metabolic effects of GLP-1RAs, including improvements in insulin sensitivity, reduction in FBG, and significant weight loss, are particularly advantageous in addressing IR: a core pathophysiological feature of PCOS that affects 75% of patients. Studies demonstrate that GLP-1RAs, especially liraglutide and exenatide, consistently promote weight reduction and improve lipid profiles, which are critical for managing obesity and MetS, common in PCOS patients.

Reproductive benefits of GLP-1RAs also show promise, with evidence indicating improvements in menstrual regularity, ovulation, and hormonal balance. Clinical trials suggest that GLP-1RAs may reduce serum androgen levels, enhance ovulatory function, and support menstrual cycle normalization. For instance, studies involving liraglutide show not only weight loss but also reductions in testosterone and LH levels, which are key in managing hyperandrogenism, a major contributor to PCOS-related infertility. Additionally, the combination of GLP-1RAs and metformin has demonstrated greater efficacy in improving ovulation rates and menstrual regularity than either drug alone.

Despite these promising outcomes, limitations exist. While animal and early human studies provide a foundation for understanding the reproductive effects of GLP-1RAs, further research is needed to validate these findings in larger, more diverse populations. Long-term studies are particularly necessary to assess the safety and efficacy of GLP-1RAs in women attempting conception or undergoing fertility treatments, as well as to establish optimal dosing regimens specific to PCOS. Additionally, the effects of GLP-1RAs on long-term cardiovascular outcomes in PCOS remain an important area for future research.

In conclusion, GLP-1RAs hold significant potential as part of a comprehensive treatment approach for PCOS, addressing both metabolic abnormalities and reproductive health challenges. By targeting IR, aiding weight management, and potentially improving fertility parameters, GLP-1RAs may offer an effective solution for PCOS patients. However, further research on their long-term safety, reproductive impact, and combination with other therapeutic agents is essential to fully integrate GLP-1RAs into standard PCOS management.

Appendix

Abbreviations

ACTH adrenocorticotropic hormone

AMH anti-Müllerian hormone

BMI body mass index

BP blood pressure

COCPs combined oral contraception pills

CPA cyproterone acetate

DHEA dehydroepiandrosterone

DHEA-S dehydroepiandrosterone sulfate

DHT dihydrotestosterone

EE ethinylestradiol

FAI free androgen index

FBG fasting blood glucose

FDA Food and Drug Administration

FN1 fibronectin 1

FSH follicular stimulating hormone

FT free testosterone

GIP glucose-dependent insulinotropic polypeptide

GLP-1 glucagon-like peptide-1

GLP-1RA glucagon-like peptide-1 receptor agonist

GLP-1RAs glucagon-like peptide-1 receptor agonists

GnRH gonadotropin-releasing hormone

HbA1c hemoglobin A1c

HDL high-density lipoprotein

HOMA-IR homeostatic model assessment of insulin resistance

HPA hypothalamic-pituitary-adrenal

HPG hypothalamic-pituitary-gonadal

IL interleukin

IR insulin resistance

IVF in vitro fertilization

LH luteinizing hormone

MetS metabolic syndrome

MR-proADM mid-regional pro-adrenomedullin

MR-proANP mid-regional pro-atrial natriuretic peptide

NAFLD nonalcoholic fatty liver disease

OCPs oral contraception pills

OGTT oral glucose tolerance test

PCOS polycystic ovarian syndrome

PIIINP procollagen type 3 amino-terminal peptide

PRDX6 peroxiredoxin 6

RAAS renin-angiotensin-aldosterone system

RCT randomized control trial

ROS reactive oxygen species

SHBG sex hormone-binding globulin

T2DM type 2 diabetes mellitus

TC total cholesterol

TG triglycerides

TNF-α tumor necrosis factor-alpha

TZDs thiazolidinediones

WC waist circumference

WHR waist-to-hip ratio