Even though obesity and PCOS are not the clinical diagnostic characteristics of each other’s conditions, the coexistence is about 30–70%. ¹⁷ The strong bidirectional network of metabolic, inflammatory, and endocrine disturbance between these two conditions further perpetuates the reproductive dysfunction synergistically. Obesity poses a significant risk for developing insulin resistance by triggering chronic low-grade systemic and local inflammation, which is a key diagnostic criterion for PCOS. ^{18 , 19} Manifested hyperinsulinemia elevates androgen levels by regulating hepatic SHBG production and raising ovarian androgen levels. ^{20 , 21} Meanwhile, PCOS promotes visceral fat accumulation through hyperandrogenism, a major driver of hyperinsulinemia. Further, obese or PCOS conditions, dysregulated hypertrophy and hyperplasia of adipose tissues actively drive chronic low-grade inflammation. ²² Collectively, these factors disrupt hormonal cascade, interfering with steroidogenesis, impairing folliculogenesis, and further worsening metabolic dysfunction, ultimately contributing to infertility in women with obesity and/or PCOS. ^{23 – 26} In addition, obesity may impact fertility by many processes, such as mitochondrial dysfunction, ²⁷ meiotic disruption, and excess androgen production in follicular thecal cells, which may result in follicular atresia and anovulation. ¹¹ Therefore, reducing body weight and improving insulin sensitivity are the key potential therapeutic approaches to address their metabolic, endocrine and reproductive health in these women. Multiple clinical studies consistently reported beneficial effects, such as improvement in menstrual cyclicity, insulin resistance, and ovulation rate post-weight loss, directing a better reproductive health in these women. ^{28 , 29} Irrespective of the beneficial effects, the adherence to the weight loss programs involving only lifestyle intervention is less, and often, dropout cases are high. ^{30 , 31} Further, lifestyle interventions alone are generally insufficient for managing long-term sustainable weight loss. ³² Therefore, pharmacotherapy combined with lifestyle intervention represents an alternative strategy to achieve weight loss. In women with obese and PCOS suffering from infertility, metformin remains the drug of choice, ³³ while ongoing research is exploring the therapeutic potential of other insulin-sensitising agents such as roflumilast, dulaglutide, exenatide, liraglutide, lixisenatide and semaglutide in the management of PCOS. In recent years, the use of anti-obesity medication has risen enormously among obese and PCOS women. Orlistat, naltrexone-bupropion, phentermine-topiramate, liraglutide, semaglutide, setmelanotide, and trizepatide are the present Food and Drug Administration (FDA) approved anti-obesity drugs. ³⁴ Advances in understanding the neuroendocrine pathways regulating hunger and satiety have further accelerated the development of these therapies, with GLP-1 receptor agonists gaining increasing attention.

Following its approval as an anti-diabetic drug by the US FDA in 2010, liraglutide was further endorsed as an anti-obesity drug in 2014, substantiated by its robust effectiveness in both glycaemic control and weight management. It is an acylated GLP-1 analogue, consisting of 31 amino acids and sharing 97% homology with endogenous GLP-1, with a half-life ranging from 11 to 15 hours, enabling once-daily subcutaneous dosing. ^{35 – 38} The primary action of the drug is regulating food intake by delaying gastric emptying, enhancing satiety, and regulating insulin and glucagon secretion from beta cells (β-cells) of the pancreas, while reducing hepatic glucose secretion, thereby contributing to weight management. ³⁷ These functions are mediated by activating a G-protein, which subsequently elevates cyclic adenosine monophosphate (cAMP) levels and activates protein kinase A (PKA), initiating a signalling cascade, that leads to the opening of voltage-gated calcium channels and increases intracellular calcium levels, which further triggers the fusion of insulin-containing vesicles with the plasma membrane and promoting insulin secretion. ³⁹ In long-term weight loss maintenance, it primarily drives sustainability by preserving leptin levels and increasing peptide YY (PYY), leading to an adaptive metabolic slowdown. ⁴⁰

In addition to its effect on appetite suppression and weight management, it demonstrates a wide range of protective effects across various tissues and cell types, including central aspects of reproductive health such as the hypothalamic-pituitary-gonadal (HPG) axis and ovarian cells. These benefits are not restricted to a single target or organ but arise through interconnecting signalling pathways. Its mechanisms involve modulation of key regulators such as AMP-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), wingless/integrated site (Wnt)/β-catenin, and autophagy-related pathways, allowing it to influence inflammation, oxidative stress, apoptosis, metabolism, and tissue remodelling in diverse biological contexts. ^{37 – 40} By targeting the central signalling cascades, liraglutide not only addresses metabolic outcomes but may also support reproductive function. ³⁷

Liraglutide has been extensively investigated for its anti-diabetic, anti-obesity, and metabolic benefits. As summarised in Table 1, clinical trials have demonstrated dose-dependent weight loss in obese and diabetic patients following subcutaneous administration. A dose-dependent weight loss was observed in subjects receiving liraglutide for 20 weeks at various doses, with a maximum reduction of 7.2 kg achieved at 3.0 mg, respectively, which notably outperforms the 2.8 kg observed in placebo and 4.1 kg with orlistat, a lipase inhibitor (120 mg, three times daily, orally), alongside an energy-deficient diet and physical activity. ⁴¹ While these results are promising, transient GI effects were more frequent in both liraglutide and orlistat compared to placebo. However, liraglutide was associated with a lower frequency of diarrhoea than orlistat and no events of acute pancreatitis were noted. The efficacy of the drug is further validated by a treatment with liraglutide (3 mg daily) for 56 weeks, which resulted in nearly triple weight reduction (8.4 ± 7.3 kg) compared to the placebo group (2.8 ± 6.5 kg), despite both groups receiving counselling for lifestyle modifications, underscoring the independent efficacy of the drug. It reduced fasting glucose, glycated haemoglobin (HbA1c), and fasting insulin levels and was associated with improved physical and mental health, thereby improving the healthy quality of life as compared to placebo. ⁴² Further long-term studies have demonstrated its beneficial effects in obese women, where 2.4 mg daily during year 1, followed by 3 mg daily in year 2, resulted in superior weight loss (7.8 kg) compared to placebo (2.0 kg) and orlistat (3.9 kg), indicating its better tolerability and sustained weight loss. ⁴³ Beyond weight management and improvements in glycemic control, 12 months of liraglutide treatment has been shown to reduce visceral adiposity, improve insulin sensitivity and β cell function in metformin-treated obese patients with prediabetes compared to lifestyle modifications alone, with comparable weight loss of 7%. ^{44 – 46} Surprisingly, in these subjects, improved insulin sensitivity was observed as early as two weeks of treatment before achieving significant weight loss. Liraglutide significantly reduced major adverse cardiovascular events, cardiovascular mortality, and nephropathy risk in T2D patients with high cardiovascular risk. ^{47 – 50} (Supplementary Table 1).

Exploring the mechanisms involved in these beneficial clinical outcomes, liraglutide exerts its actions by modulating several key pathways, as summarized in Figure 2, while supplementary Table 1 details the liraglutide- mediated mechanistic orchestration. One strategic way by which liraglutide drives anti-obesity effects is through modulation of fat metabolism and reduction of insulin resistance. Liraglutide upregulates brown fat differentiation, promoting thermogenesis in brown adipose tissue (BAT) via activation of soluble guanylyl cyclase (sGC)/cyclic guanosine phosphate (cGMP)/PKA signalling pathway. ⁵¹ This increases energy expenditure and heat production mediated by downregulation of miR-27b which facilitates the browning of white adipose tissue. ⁵² Tin addition, liraglutide upregulates adenylate cyclase 3 (AC3) ⁵³ at both hepatic and serum levels, indicating a coordinated metabolic regulation.

Liraglutide suppresses gluconeogenic enzymes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase via the Wnt/β-catenin pathway, while enhancing expression of glucose transporter type 4 (GLUT4) in both liver and skeletal muscle. ^{54 , 55} It also augments glycolysis and glycogenesis via activation of hexokinase and pyruvate kinase while preserving pancreatic β-cell mass by inhibiting apoptosis through the cAMP-PI3K pathway and increasing proliferation through reducing oxidative stress. ^{56 , 57} It activates autophagy via AMPK and transcription factor EB (TFEB), promoting lysosomal biogenesis and lipid clearance, thus preventing hepatic lipid accumulation. ^{58 , 59} In adipose tissue, it activates fibroblast growth factor 21 (FGF21)/liver kinase B1(LKB1)/AMPK/acetyl-CoA carboxylase 1 (ACC1) axis, thus reducing lipogenesis, promoting fatty acid oxidation, and suppressing pro-inflammatory signalling. ⁶⁰ It also reduces β-site amyloid precursor protein cleaving enzyme 1 (BACE1) activity, thereby exhibiting a neuroprotective action. ⁶¹ Higher leptin levels observed in both PCOS and obese conditions inhibit follicular growth as well as hinder oocyte maturation. ⁶² Liraglutide in obese mice combats impaired leptin signalling through the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2-STAT3) signalling pathway, lowers expression of improves insulin resistance, lowers fasting insulin levels, decreases hyperandrogenism, and improves menstrual cyclicity pattern, thereby creating a favourable environment relevant to improving reproductive health. ^{63 – 68}

Liraglutide demonstrates strong anti-inflammatory activity in PCOS and obese conditions. In human chondrocytes, it inhibits nuclear factor κB (NF-κB)/tumour necrosis factor-alpha (TNF-α) signalling pathway, thereby attenuating extracellular matrix (ECM) proteins degradation and advanced glycation end products (AGE)-induced apoptosis. ⁶⁹ Similarly, in fibroblasts, liraglutide attenuates collagen overproduction by modulating the cluster of differentiation 36 (CD36)/c-Jun N-terminal kinase (JNK)/activator protein 1 (AP1) pathway. ⁷⁰ In addition, it suppresses Wnt/β-catenin and Toll-Like Receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/NF-κB inflammatory cascade to reduce ECM deposition and pro-inflammatory cytokine expression. ^{71 , 72} It also reduces sclerosis and autophagy in renal cells, ⁷³ while in the vasculature, it reduces inflammatory marker expression in obese conditions. ⁷⁴ Further, it enhances bone mineral density and decreases bone resorption, thereby protecting against osteoporosis. ⁷⁵ Its neuroprotective effects have also been reported, with improved neuronal cell survival and repair via cAMP/PKA,CREB and Wnt signalling pathways. ^{76 – 79} In spinal cord and hypoxic ischemic injuries, it preserves tissue integrity by activation of AMPK/Forkhead Box O3 (FOXO3) mediated autophagy and PI3K/Akt/glycogen synthase kinase 3 β (GSK3β) signalling, respectively. ^{80 , 81} It reverses synaptic loss and memory impairment, improves cognition and motor coordination. ^{82 – 84} While these multi-organ effects range from neuroprotection to bone remodelling, highlighting the systemic versatility of liraglutide, they serve as parallel evidence of liraglutide’s ability to conserve and restore cellular homeostasis.

The anti-inflammatory profile of liraglutide is very relevant, and it lowers the level of C-X-C motif chemokine ligand 10 (CXCL10) by blocking the JAK signalling pathway in PCOS condition. ^{85 , 86} It also exhibits potent anti-inflammatory effects by inhibiting the NF-kB and TNF-α pathways, accompanied by upregulation of sirtuin 1 (SIRT1) and increased phosphorylation of insulin receptor substrate (IRS-1). ^{87 – 89} Furthermore, the beneficial effect of liraglutide on decreased inflammation is by lowering key proinflammatory markers, including interleukin-6 (IL-6), interleukin-1beta (IL-1β), and chemokine C-C motif ligand 2 (CCl2). ⁹⁰ Overall, liraglutide highlights the anti-inflammatory effects at both systemic and organ levels, balancing the inflammatory milieu. ^{91 – 94} However, it also warrants further investigation into its effects on ovarian oxidative stress and granulosa cell survival to optimize the use of the drug in correcting reproductive dysfunction in obesity and PCOS conditions.

Liraglutide alters the overall diversity and abundance of gut microbiota, elevates well-known probiotics, ^{95 , 96} promotes bacteria-derived butyrate production and improves lipid profile, inducing weight reduction, regulates glucose metabolism, and reduces insulin resistance and hyperandrogenism, ultimately promoting better metabolic health in obese, PCOS, and diabetic condition. ^{97 – 103} Its effect is mediated by enrichment of the phylum Bacillota, leading to a reduced Bacilliota to Bacteroidota ratio, which is usually lower in the PCOS condition. ^{104 – 106} Clinical trials involving liraglutide have been linked to improved ovarian morphology and function, as well as the restoration of regular menstrual cyclicity. ⁶⁸ These improvements are likely mediated through modulating gut microbiota, which in turn influences hormonal balance and systemic inflammation. However, further clinical trials are warranted to confirm the therapeutic effects of liraglutide.

One of the promising strategies of liraglutide in improving reproductive health is hormone profile modification by interconnected metabolic and endocrine modifications ( Figure 3). Hyperinsulinemia and elevated LH secretion in obese and PCOS are the key mediators of ovarian-associated hyperandrogenism. Liraglutide reduces adipose tissue inflammation and lipotoxicity and thereby decreases hyperinsulinemia and improves insulin sensitivity, ¹⁰⁷ which in turn reduces androgen synthesis by following the PI3K pathway mediated CYP17 driven androgen synthesis activity. ¹⁰⁸ It also improves insulin resistance and elevates SHBG, thereby reducing androgen levels and resulting in a lowered free androgen index. ^{109 – 112} Furthermore, anti-mullerian hormone (AMH) produced by granulosa cells stimulates the pulsatile release of gonadotropin-releasing hormone (GnRH) and downstream gonadotrophins (LH and FSH), which are closely associated with the maintenance of ovarian reserve and function. Notably, AMH levels are often elevated in obese women with PCOS. ^{113 , 114} Marking all the positive alterations in terms of improving the hormonal index, thereby supporting folliculogenesis, liraglutide may be a useful treatment choice for women undergoing PCOS & obesity ( Figure 3).

In addition, liraglutide reduced methylation of the leptin promoter in ovarian granulosa cells in PCOS conditions, which was positively connected to higher ovulation rates, better hormonal profiles, and spontaneous conception. ¹¹⁵ However, the translational impact of the findings is constrained by the small sample size and retrospective design, which limits the generalizability. It alters the phosphorylation status of FoxO1, a known negative regulator of cell survival, by promoting Akt-mediated phosphorylation. This leads to reduced expression of pro-apoptotic genes Bim and FasL, decreases apoptosis of granulosa cells, and thereby improves folliculogenesis. ¹¹⁶ Liraglutide restores the interaction between granulosa cells and oocytes, which is essential for oocyte growth, by improving the expression of the gap junction protein alpha 1 (GJA1) ⁸⁶ and ferredoxin 1 (FDX1), the latter being critical for p450 enzyme activation in PCOS conditions. ¹¹⁷ It also reversed PCOS-induced downregulation of steroidogenic enzymes, namely cholesterol side-chain cleavage enzyme (CYP11A1) and aromatase (CYP19A1) and impaired follicular development. The restoration of these enzymes led to improved estradiol synthesis, folliculogenesis and overall reproductive health. These beneficial effects of liraglutide are further driven by its potential anti-inflammatory effect, which favourably enables the ovarian microenvironment for promoting folliculogenesis and ovulation. Collectively, these beneficial effects position liraglutide as a potential therapeutic option for improving follicular growth in PCOS.

Recent studies have underlined several specific mechanisms through which liraglutide improves ovarian health by supporting follicular development ( Figure 2). Liraglutide reduced methylation of the LEP (leptin) promoter in ovarian granulosa cells in PCOS conditions, ¹¹⁴ which positively connected to higher ovulation rates, better hormonal profiles, and spontaneous conception. It alters the phosphorylation status of forkhead box protein O1 (FoxO1), a known negative regulator of cell survival, by promoting Akt-mediated phosphorylation, resulting in reduced expression of pro-apoptotic genes such as Bim and FasL, resulting in decreased apoptosis of granulosa cells and improved folliculogenesis. ¹¹⁵ The administration of Liraglutide restores the equilibrium between granulosa cells and oocytes by improving the expression of the gap junction protein alpha 1 (GJA1) in PCOS conditions through the JAK) signaling pathway. ⁸⁶ Importantly, it upregulated Ferredoxin 1 (FDX1) expression in PCOS condition, a protein critical for p450 enzyme activation, which is suppressed in this condition. ¹¹⁶ It also reversed PCOS-induced downregulation of steroidogenic enzymes namely cholesterol side-chain cleavage enzyme (CYP11A1) and aromatase (CYP19A1) and impaired follicular development. The restoration of these enzymes led to improved estradiol synthesis, folliculogenesis and overall reproductive health. These beneficial effects liraglutide are further driven by its potential anti-inflammatory effect, which favorably enables the ovarian microenvironment for promoting folliculogenesis and ovulation. The dual function of liraglutide, in increasing granulosa cell survival and reducing inflammation, makes it a potential therapeutic option for improving follicular growth in PCOS conditions.

Clinical trials assessing the effect of liraglutide on metabolic, hormonal, and reproductive function in obese and PCOS women

While the mechanistic plausibility of liraglutide in preclinical models is robust, the clinical validation in PCOS/obese population remains a landscape of promise, and available evidence is contingent on methodological heterogeneity. Liraglutide has demonstrated promising effects in improving metabolic and reproductive parameters in non-diabetic women with obesity and PCOS ( Table 2). A randomized, placebo-controlled phase 3 clinical trial involving 82 obese and PCOS patients reported a significant weight reduction in the liraglutide group, compared to the placebo group, leading to regular menstrual cyclicity with two participants achieved spontaneous conception. ⁶⁷ Effects like lowered testosterone, improved insulin resistance, improved lipid profile and adiposity, improved menstrual cyclicity with one participant achieving pregnancy and delivering a healthy child were pronounced in an extreme case of PCOS with endocrine disorder depicted by HAIR-AN syndrome. Interestingly, these benefits occurred with minimal weight loss following post-liraglutide treatment in these patients underscoring its pharmacologic effects independent of weight reduction. ⁶⁸ In a study involving 72 overweight women with PCOS, liraglutide led to reduction in body weight. Increase in SHBG level and decrease in free testosterone level. Although it did not improve insulin sensitivity, reductions in fasting glucose and leptin levels were observed. This study did not elaborate on reproductive functions as well as hormone levels. ¹⁰⁹ Furthermore, in a cohort of 30 obese PCOS patients, liraglutide was superior to metformin in improving glucose metabolism, lipid profiles, and BMI, as well as reducing leptin promoter methylation in granulosa cells, thereby increasing leptin secretion in these cells. Moreover, significant reductions in FSH, LH, and E2 levels were observed after liraglutide intervention, alongside improved menstrual regularity, ovulation rates, and natural pregnancy occurrences. ¹¹⁰ However, this study lacked a placebo group, had a small sample size. In another study involving obese women with PCOS, liraglutide treatment resulted in greatest weight loss, followed by roflumilast and metformin, with metformin showing the least among the three treatment groups. All three treatment groups experienced improvements in menstrual regularity. However, roflumilast had a significant upper hand over the liraglutide arm. No significant intergroup differences in free testosterone, SHBG, androstenedione, dehydroepiandrosterone (DHEA), FSH, and LH were observed. In addition, improved glucose homeostasis was found in liraglutide patients compared to metformin and roflumilast subjects. However, this study had a few limitations, including a small sample size, short duration, open-label nature of the study, and lack of active lifestyle promotion. ¹¹⁷ In contrast, placebo-controlled, randomized trial involving 65 overweight PCOS women treated with liraglutide for 26 weeks showed average weight loss, improved fasting glucose, improved insulin sensitivity, menstrual regularity and normalization of AMH level. Further, three-dimensional ultrasound revealed a decrease in both total ovarian volume and stromal volume. However, this study also had a limitation of participant selection bias, as partial recruitment was by social media, and lifestyle changes were not actively promoted throughout the study. ¹¹⁸ Among the Chinese population, the combination therapy of metformin and liraglutide has proved its efficacy in weight loss and improving hyperandrogenemia, including total testosterone, free androgen index, and SHBG levels and showed a menstrual cycle recovery rate of 92.59%, whereas the metformin alone group showed 88% recovery rate. ¹¹⁰ Nevertheless, limitations included the absence of a control group, potential selection bias, lack of fertility outcome data, short follow-up duration, and their small sample size, single-center design. In addition, this study did not assess key reproductive parameters such as ovulation or pregnancy outcomes.

Adding on, the combination of liraglutide with metformin, appears to offer synergistic benefits on metabolic and reproductive outcomes in obese women with PCOS. Combination of liraglutide and metformin not only offers superior glycemic control more effectivly but also provides a significant advantage in promoting body weight loss, emphasizing its role in metabolic regulation in comparison to placebo, sitagliptin, glimepiride, dulaglutide, insulin glargine, and NPH insulin. ^{119 , 120} Importantly, the combined treatment did not increase the risk of hypoglycemia but induced a higher incidence of adverse effects of gastrointestinal disturbances, such as nausea, compared to metformin. However, the severity of these adverse effects was reduced over time. ¹²¹ Nevertheless, limitations included the absence of a control group, potential selection bias, lack of fertility outcome data, short follow-up duration and their small sample size, single-center design. ¹²² Few studies did not assess key reproductive parameters such as ovulation, menstrual cyclicity, or pregnancy outcomes. Subsequently infertile obese PCOS patients treated either with metformin in combination with low-dose liraglutide, resulting in markedly higher pregnancy rates per embryo transfer in the liraglutide despite similar reductions in weight and visceral adiposity. ¹²³ Higher cumulative pregnancy rates are supported by improved menstrual cycle regularity, glucose metabolism, and modulation of LH and progesterone levels. These findings suggest liraglutide or in combination with metfromin is effective for weight reduction and regulated hormonal balance in women with obesity and PCOS, which supports its potential as a therapeutic option that may exert beneficial effects on reproductive outcomes in women with metabolic disorders, providing a potential therapeutic option for addressing infertility in this population.