GLP-1 Receptor Agonists and Reproductive Health: Links Between IVF, Ovary Function, and Molecular Actions

Glucagon-like peptide-1 (GLP-1) is an incretin hormone synthesised by enteroendocrine L-cells in the distal ileum and colon in response to food consumption, particularly carbs and fats. Upon its release, GLP-1 regulates nutrition utilisation, energy storage, and metabolic stability via several endocrine and paracrine mechanisms [1]. Dipeptidyl peptidase-4 (DPP-4) rapidly degrades the peptide, resulting in a brief physiological half-life of around 1–2 min. This issue has been addressed by pharmacological GLP-1 receptor agonists (GLP-1RAs) with an extended duration of action [2]. The GLP-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) mostly associated with Gαs proteins. It activates adenylate cyclase and increases intracellular cyclic AMP (cAMP) levels [3]. cAMP augments insulin gene transcription, insulin granule exocytosis, and β-cell survival in pancreatic β-cells by activating protein kinase A (PKA) and exchange protein activated by cAMP (EPAC) via anti-apoptotic pathways (e.g., PI3K/AKT). GLP-1 inhibits α-cells from secreting glucagon, delays gastric emptying, and modifies the hypothalamic satiety centres via both vagal afferent and central pathways [4]. GLP-1 signalling alters the NF-κB, c-Jun N-terminal kinase (JNK), and mitogen-activated protein kinase (MAPK) pathways, producing effects that extend beyond glucose regulation, including the reduction in inflammation, oxidative stress, and atherosclerosis.

Researchers have identified GLP-1R expression in adipose tissue, cardiomyocytes, endothelial cells, the renal system, and the central nervous system. This indicates that it is not only located in metabolic organs [5]. These extrapancreatic actions enhance insulin sensitivity, improve lipid metabolism, reduce systemic inflammation, and regulate autonomic output. Activation of GLP-1R in adipocytes inhibits the activity of pro-inflammatory cytokines such as TNF-α and IL-6, while initiating lipolysis, browning, and the secretion of adiponectin [6]. Liraglutide, semaglutide, dulaglutide, and exenatide are pharmacological agents classified as GLP-1RAs. They are engineered to withstand DPP-4 degradation and possess half-lives ranging from hours to days. Their therapeutic outcomes include substantial weight reduction, decreased visceral fat, improved blood glucose levels, reduced fatty liver disease, and enhanced cardiovascular and metabolic health. The circuits governing reproductive physiology are intricately connected to these systemic improvements [7]. Enhanced insulin sensitivity mitigates ovarian androgen surplus induced by excessive insulin, whereas reduced inflammation in adipocytes restores the normal signalling of the hypothalamic-pituitary-ovarian axis (HPO). GLP-1 traverses the blood–brain barrier, influencing hypothalamus nuclei that regulate the pulsatility of gonadotropin-releasing hormone (GnRH) [8]. GLP-1 may indirectly support ovulatory function by improving metabolic signals that link peripheral nutrition status with reproductive preparedness.

Obesity significantly impacts the female reproductive system by influencing the HPO axis via metabolic, endocrine, and inflammatory mechanisms. Individuals who are overweight or obese have persistent low-grade inflammation and insulin resistance, resulting in elevated insulin levels [9]. Elevated concentrations of insulin and luteinizing hormone (LH) synergistically enhance the activity of CYP17A1 in ovarian theca cells, resulting in excessive androgen synthesis. Hyperandrogenism impedes anovulation, granulosa cell development, and folliculogenesis [10]. Insulin inhibits the liver's production of sex hormone-binding globulin (SHBG), exacerbating the hyperandrogenic condition by increasing the concentration of free androgens in the bloodstream. Adipose tissue functions as an active endocrine organ, synthesising adipokines including leptin, adiponectin, resistin, and pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [11]. These chemicals may affect reproductive function. Insufficient adiponectin levels diminish insulin-sensitizing signals and exacerbate metabolic issues. Alterations in leptin signalling, conversely, affect the dynamics of GnRH pulses and the functioning of LH/FSH. Visceral fat exacerbates these effects by inducing oxidative stress, impairing mitochondrial function, and altering the expression of steroidogenic enzymes in the ovary.

PCOS exemplifies the connection between metabolism and reproduction. Between 8% and 13% of women of reproductive age are affected by it. PCOS is characterised by chronic anovulation, elevated androgen levels in the bloodstream or body, and a polycystic ovarian morphology [12]. It is often associated with insulin resistance and metabolic syndrome. Impairments in granulosa cell signalling, such as deregulation of the PI3K/AKT pathway, elevated concentrations of anti-Müllerian hormone (AMH), and aberrant FSH-mediated aromatase activity, lead to follicular stoppage in the early antral stage [13]. In PCOS, the ovarian environment demonstrates increased oxidative stress, mitochondrial impairment, and modifications in autophagic and apoptotic pathways. All of these factors diminish the efficacy of oocytes in performing their function. These alterations in metabolism and hormones extend beyond the ovary [14]. Obesity and PCOS alter the expression of progesterone receptors, integrin profiles, vascular remodelling, and local inflammatory signalling, rendering the endometrium less susceptible. Consequently, both natural conception and assisted reproduction provide worse outcomes. Obese women undertaking IVF often need more gonadotropin dosages, yield a diminished number of mature oocytes, generate embryos of worse quality, and encounter decreased implantation and live birth rates. Long-term metabolic inflammation and inadequate luteal function have been associated with an elevated risk of miscarriage [15].

Weight reduction is a crucial factor in assisting obese individuals and those with PCOS in achieving pregnancy. Reducing body weight by as little as 5–10% might enhance menstrual regularity, boost ovulation frequency, and elevate the incidence of clinical pregnancies. However, it remains challenging to lose weight and maintain that loss, underscoring the need of discovering methods to enhance metabolism [16]. GLP-1 receptor agonists effectively mitigate the metabolic factors contributing to reproductive dysfunction by enhancing insulin efficacy, reducing inflammation in adipocytes, and specifically targeting visceral fat. The modifications to the whole system amplify and increase the likelihood of direct effects on the ovaries resulting from GLP-1R signalling [17].

Although GLP-1R has traditionally been studied in pancreatic, gastrointestinal, and neurological tissues, recent findings reveal the existence of GLP-1R in the ovary, particularly in the GCs of developing follicles. This discovery presents a physiologic basis for the potential direct effect of GLP-1Ras on the ovaries, irrespective of enhancements in systemic metabolism [18]. The presence of GLP-1R in the ovaries suggests that incretin signalling may affect essential pathways regulating follicular survival, steroidogenesis, and oocyte maturation. GLP-1R is a type B G protein-coupled receptor that primarily induces the accumulation of cAMP inside cells by activating the Gαs-adenylate cyclase pathway. cAMP serves as a crucial second messenger in granulosa cells [19]. It governs the production of steroid hormones, the expression of aromatase, and differentiation mediated by FSH. GLP-1R signalling may modulate essential activities like GC proliferation, apoptosis, and gonadotropin responsiveness via the activation of PKA and exchange protein directly activated by cAMP (EPAC) downstream.

Experimental findings indicate that a primary downstream target of GLP-1R signalling is FOXO1, an essential transcription factor crucial for GC apoptosis and cell cycle control. In murine models of PCOS, the injection of GLP-1RA enhances FOXO1 phosphorylation, leading to its exclusion from the nucleus and ultimately diminishing its pro-apoptotic function [18]. This process enhances the viability of granulosa cells, perhaps facilitating follicular maturation. The heightened death of granulosa cells often seen in PCOS, associated with oxidative stress, hyperandrogenism, and metabolic dysregulation, may be alleviated by these anti-apoptotic actions [20]. The BMP-Smad pathway, an essential regulator of ovarian steroidogenesis, concurrently interacts with GLP-1 signalling. GLP-1 inhibits FSH-induced progesterone production in in vitro models by reducing the expression of steroidogenic enzymes, such as StAR, P450scc, and 3β-HSD. Augmented BMP-Smad1/5/8 activation inhibits progesterone production, hence contributing to this suppression. The results suggest that incretin signalling may precisely regulate steroidogenic production via the interaction of FSH-cAMP and BMP-Smad pathways, leading to a context-dependent alteration of follicular endocrine function [21].

The effect of GLP-1RAs on the ovaries is markedly affected by the physiological setting, treatment period, and dose given. Certain studies indicate that liraglutide may be beneficial by accelerating the proliferation of granulosa cells, inhibiting apoptosis, and enhancing follicular development. However, further research, particularly with animals given high doses of liraglutide, indicates potential adverse effects. These factors include heightened oxidative stress, mitochondrial dysfunction, granulosa cell death, and modified ovarian shape, all indicating that excessive or extended exposure to GLP-1RA may disturb ovarian homeostasis.

GLP-1RAs have garnered interest in reproductive medicine for their ability to mitigate the interrelated metabolic, endocrine, and ovarian dysfunctions that contribute to various forms of female infertility, particularly those associated with obesity and PCOS [22]. GLP-1RAs demonstrate several advantages, including substantial weight reduction, enhanced insulin sensitivity, less systemic inflammation, and the reinstatement of metabolic indicators associated with ovarian dysfunction. Enhancing metabolism using GLP-1 receptor agonists offers a solid theoretical basis for enhancing reproductive outcomes, given that obesity and insulin resistance affect follicular maturation, ovulation, egg quality, and endometrial receptivity [23].

Additionally, GLP-1 receptor agonists seem to provide reproductive advantages with systemic metabolic enhancement. Clinical investigations indicate that GLP-1 receptor agonists assist overweight or obese women with PCOS in achieving more regular menstrual cycles, increased spontaneous ovulation, reduced excess testosterone levels, and normalised gonadotropin-independent ovarian function [22,24]. These enhancements indicate intragonadal mechanisms that might enhance systemic effects. Preliminary findings indicate that GLP-1RA medication combined with metformin enhances IVF-related outcomes, including the pregnancy rate per embryo transfer, despite equivalent weight reduction across treatment groups. The results suggest that GLP-1 receptor agonists may influence endometrial or follicular biology in ways not exclusively linked to variations in body adiposity [25].

Mechanistic evidence supports this notion. The presence of GLP-1 receptors in granulosa cells indicates that GLP-1 receptor agonists might directly affect ovarian mechanisms governing steroidogenesis, follicular maturation, and granulosa cell survival. In PCOS models, GLP-1R activation has been shown to alter FOXO1 phosphorylation, diminish apoptosis, and promote cellular proliferation [18]. Conversely, investigations demonstrate that supraphysiological dosages of GLP-1 receptor agonists may cause granulosa cell degeneration, increase oxidative stress, and alter the expression of steroidogenic enzymes. This duality illustrates the complexity of GLP-1RA activity in reproductive organs and underscores the significance of dosage, treatment duration, and physiological environment [26].

There are considerable apprehensions about the safety and effectiveness of GLP-1RAs during ovarian stimulation, early pregnancy, and ART, especially due to their rising use among women of reproductive age, frequently commenced for weight reduction rather than diabetes treatment [27]. Notwithstanding encouraging first results, there is a deficiency of data about their effects on egg quality, embryo development, endometrial receptivity, or peri-implantation physiology in women devoid of PCOS. The lack of comprehensive mechanistic research in human ovarian tissue hinders the distinction between direct and indirect effects.

In reproductive medicine, GLP-1 receptor agonists were initially conceptualised in early integrative and narrative studies primarily as metabolic agents that indirectly improved ovulatory function and fertility by facilitating weight loss, insulin sensitisation, and systemic endocrine normalisation in obese women and patients with PCOS. This significant research established the foundation for the metabolic-reproductive axis and showed that obesity and insulin resistance are primary factors contributing to ovarian dysfunction.

However, mounting experimental and translational evidence suggests that GLP-1 receptor signalling may have direct intra-ovarian effects on granulosa cell viability, steroidogenic enzyme expression, and gonadotropin responsiveness. This systematic review enhances early integrative perspectives by offering a structured synthesis of clinical IVF results with mechanistic in vitro and in vivo findings. It also illustrates the evolution of the science from examining metabolic connections to investigating molecular and ovarian-specific processes.

This systematic review aims to thoroughly assess the clinical, translational, and molecular effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on reproduction. This review seeks to consolidate information on three main enquiries: (i) the effectiveness of GLP-1 receptor agonists in improving reproductive and IVF outcomes in women of reproductive age, especially those with obesity or polycystic ovary syndrome; (ii) the influence of GLP-1 signalling on ovarian physiology at cellular and molecular levels, including granulosa cell survival, steroidogenesis, and gonadotropin responsiveness; and (iii) the safety implications derived from findings in experimental animals and in vitro studies.

We comprehensively included randomised clinical trials, observational human studies, animal models, and in vitro studies that assessed the effects of GLP-1 receptor agonist exposure on reproductive, ovarian, hormonal, or fertility-related outcomes. This comprehensive method was designed to clarify the therapeutic potential and biological constraints of GLP-1 receptor agonists in female reproductive health, while synthesising clinical data with molecular insights.

A total of 1284 records were identified in the database searches, and manual reference filtering uncovered an additional 7 records. Subsequent to the elimination of 312 duplicates, 979 titles and abstracts were examined. 942 of these were excluded due to their non-original nature (reviews, comments, or editorials), lack of discussion on ovarian or reproductive outcomes, or failure to use GLP-1 receptor agonists. We assessed the eligibility of the remaining 37 full-text papers. Twenty-eight studies were rejected for failing to identify the effects of GLP-1 signalling, using DPP-4 inhibitors without analysing GLP-1 receptor agonists, including inappropriate populations, or lacking relevant reproductive outcomes. Nine research three randomised clinical trials, one human observational study, three in vivo animal studies, and two in vitro granulosa cell investigations satisfied the inclusion criteria., the PRISMA flow diagram, illustrates the comprehensive process of selecting research. Figure 1

This paper provides valuable insights into the direct effects of GLP-1RA treatment on the ovaries, complementing the metabolic and clinical findings from human trials with in vivo animal investigations. The data indicates a diverse, dose-dependent, and context-sensitive range of ovarian responses, from possibly beneficial regulatory effects to significant histopathological changes, despite the limited number of current investigations. The research by Saber et al. offers the most comprehensive evaluation of uterine and ovarian morphology in female rats after liraglutide treatment [32]. Prolonged exposure resulted in a consistent pattern of ovarian disruption, characterised by granulosa-cell death, increased follicular atresia, vacuolar degeneration, and disorganisation of follicular architecture. Significant alterations occurred in the endocrine system, alongside these structural issues. Rats administered liraglutide had reduced levels of FSH, LH, oestradiol, and progesterone, while displaying elevated testosterone levels. This indicates that their hormones shifted to a more androgenic character and their ovaries ceased steroid production. The alterations were associated with indicators of heightened oxidative stress, including elevated malondialdehyde (MDA) levels and diminished antioxidant defences such as glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). This indicates that exposure to GLP-1RA may intensify oxidative damage in the ovarian milieu.

Despite the adverse effects, the research indicated that some might be ameliorated after the cessation of medication. This was shown by the improvement of several hormonal disorders and histological lesions throughout the recovery period. This study underscores the dynamic characteristics of GLP-1RA effects and the importance of exposure length when applied to human physiology. The findings from the research conducted by Sun et al. in a PCOS mouse model markedly contrasted with those of Saber et al. [18,32]. Under certain doses and metabolic settings, GLP-1RA exposure enhanced granulosa cell proliferation and reduced apoptosis by facilitating the phosphorylation and nuclear exclusion of FOXO1, a critical pro-apoptotic transcription factor. GLP-1 signalling may protect ovaries affected by metabolic imbalance. This is shown by the activation of supplementary signalling pathways linked to anti-inflammatory and antioxidant responses. The data indicate that the effects of GLP-1RA may differ markedly between ovaries exhibiting insulin resistance or PCOS and healthy ovarian tissue, suggesting that therapeutic advantages may be limited to certain metabolic conditions.

This review's in vitro findings provide critical mechanistic insights into the molecular effects of GLP-1 and its receptor agonists on granulosa cell function. These findings are significant as they elucidate whether the activation of GLP-1R has direct effects on the ovarian follicle and facilitate the investigation of signalling pathways independent of systemic metabolic influences. All in vitro findings indicate that GLP-1 signalling influences several intracellular mechanisms that regulate the development, apoptosis, steroidogenesis, and responsiveness of granulosa cells to gonadotropins. Sun et al. performed a comprehensive mechanistic investigation, demonstrating that the activation of GLP-1R in granulosa cells results in the phosphorylation of the transcription factor FOXO1, leading to its eventual exclusion from the nucleus. Translocating FOXO1 from the nucleus diminishes the expression of pro-apoptotic genes and enhances cell survival, since it serves as a crucial regulator of apoptosis, cell-cycle arrest, and metabolic stress responses in granulosa cells. In a biological setting similar to PCOS, GLP-1RA administration promoted granulosa cell proliferation and provided resistance to apoptosis via this route. These results indicate that GLP-1 receptor agonists may improve follicular health in insulin-resistant or hyperandrogenic ovaries by restoring proliferative capability and diminishing intrinsic apoptotic stress.

Nishiyama et al.'s study on the involvement of incretins, such as GLP-1 and GIP, in steroidogenesis control reveals more molecular complexities [31]. Their research shown that GLP-1 inhibits granulosa cells from producing progesterone in response to FSH stimulation by reducing the activity of key steroidogenic enzymes such as 3β-HSD, P450scc, and StAR. The observed effects, associated with reduced intracellular cAMP levels, indicated a potential inhibitory interaction between GLP-1R signalling and the conventional FSH–cAMP–PKA pathway, which facilitates luteinisation and progesterone synthesis. Both GLP-1 and GIP reduced progesterone levels. On the other hand, they had divergent effects on BMP-Smad signalling. GIP, unlike GLP-1, enhanced the activation of Smad1/5/8 induced by BMP-6. This indicates that BMP receptor signalling may be altered by various ligands. This selective interaction may elucidate the divergent steroidogenic effects of GLP-1 and GIP, since BMP-Smad pathways are acknowledged to inhibit progesterone production. The intricacies highlight that intracellular context, ligand specificity, and receptor expression all influence incretin signalling in granulosa cells.

In vitro results indicate that GLP-1 signalling regulates the expression of BMP Type-I receptors, namely ALK-3 and ALK-6. These receptors subsequently alter the response of granulosa cells to local ovarian growth stimuli. Granulosa cells treated to GLP-1 or GIP exhibit increased sensitivity of their receptors to BMP-mediated suppression of steroidogenesis. The alterations, along with a reduction in the expression of inhibitory Smad6, indicate that incretin signalling is integral to a complex regulatory framework that modifies the equilibrium between BMP-mediated inhibition and gonadotropin-induced progesterone synthesis. Besides steroidogenesis and apoptosis, GLP-1 signalling also influences oxidative stress responses. Data from comparable models suggest that GLP-1/GLP-1RA administration affects mitochondrial activity, the production of reactive oxygen species, and the expression of antioxidant enzymes; this has not been definitively shown by direct in vitro research. These molecular pathways need more examination, since oxidative equilibrium is essential for granulosa cell functionality and oocyte competence.

This review of clinical, animal, and in vitro research presents a complex and context-dependent overview of the impact of GLP-1RAs on the female reproductive system. In human clinical studies, GLP-1RA medication consistently improved metabolic status, reduced androgen excess, restored menstrual cyclicity, increased ovulation rates, and boosted both spontaneous and assisted conception results. The benefits were sometimes disproportionate to the extent of weight reduction, indicating supplementary reproductive processes beyond just metabolic adjustment. The results illustrate the therapeutic advantages of GLP-1 receptor agonists for women with PCOS and metabolic dysfunction, whereby anovulation and diminished fertility are mostly associated with insulin resistance and hyperandrogenism.

The molecular and cellular insights derived from in vitro studies provide the mechanistic foundation for these clinical progressions. Investigations involving granulosa cells reveal that GLP-1 signalling affects essential intracellular pathways governing apoptosis, proliferation, and steroidogenesis. Activation of GLP-1R prevents the apoptosis of granulosa cells by phosphorylating FOXO1, therefore sequestering it in the cytoplasm and excluding it from the nucleus. It also interacts with the cAMP-PKA and BMP-Smad pathways to maintain equilibrium between FSH-induced steroidogenesis and local intra-ovarian signalling. The incretin-mediated modulation of enzymes such as StAR, P450scc, and 3β-HSD clarifies clinical endocrine improvements, including the normalisation of SHBG, decrease in free testosterone, and augmentation of ovulatory dynamics.

In vivo animal studies elucidate these molecular results and illustrate the dualistic nature of GLP-1RA activity. GLP-1 signalling enhanced follicular health in models that were metabolically impaired or analogous to PCOS, aligning with the observed benefits in individuals with PCOS. The impact of GLP-1RA is significantly influenced by metabolic condition, length of therapy, and physiological setting. Studies on healthy rats given supra-physiological dosages of liraglutide demonstrated ovarian disturbance, indicated by increased follicular atresia, oxidative damage, hormonal suppression, and structural disorganisation. This disparity suggests that GLP-1 receptor agonists may be advantageous for insulin-resistant ovaries but perhaps detrimental to normal ovarian tissue under certain circumstances. This review presents a complex and context-dependent overview of the impact of GLP-1RAs on the female reproductive system, as shown by clinical, animal, and in vitro investigations. In human clinical studies, GLP-1RA medication consistently improved metabolic status, reduced androgen excess, restored menstrual cyclicity, increased ovulation rates, and boosted both spontaneous and assisted conception results. The benefits were sometimes disproportionate to the extent of weight reduction, indicating supplementary reproductive processes beyond just metabolic adjustment. The results illustrate the therapeutic advantages of GLP-1 receptor agonists for women with PCOS and metabolic dysfunction, whereby anovulation and diminished fertility are mostly associated with insulin resistance and hyperandrogenism.

The molecular and cellular insights derived from in vitro studies provide the mechanistic foundation for these clinical improvements. Investigations involving granulosa cells reveal that GLP-1 signalling affects essential intracellular pathways governing apoptosis, proliferation, and steroidogenesis. Activation of GLP-1R prevents the apoptosis of granulosa cells by phosphorylating FOXO1, therefore sequestering it from the nucleus. It also interacts with the cAMP-PKA and BMP-Smad pathways to maintain the equilibrium between FSH-mediated steroidogenesis and local intra-ovarian signalling. The modulation of enzymes such as StAR, P450scc, and 3β-HSD by incretins clarifies clinical endocrine improvements, including the normalisation of SHBG, a decrease in free testosterone, and promotion of ovulatory processes.

In vivo animal studies elucidate these molecular results and illustrate the dualistic nature of GLP-1RA activity. GLP-1 signalling enhanced follicular health in animals exhibiting metabolic compromise or characteristics akin to PCOS, aligning with the observed benefits in individuals with PCOS. The effects of GLP-1RA are significantly influenced by metabolic state, length of therapy, and physiological setting. Investigations on healthy rats given supra-physiological dosages of liraglutide indicated ovarian disturbance, characterised by increased follicular atresia, oxidative damage, hormonal suppression, and structural disorganisation. This disparity indicates that GLP-1 receptor agonists may assist ovaries unresponsive to insulin; they may adversely affect normal ovarian tissue in some instances. The main Findings of our research are presented on Table 3.

Examining the molecular data from Sun, Nishiyama, Xiong, Saber, and Yin reveals that GLP-1 receptor agonists have both analogous and divergent effects on ovarian and reproductive organs [18,31,32,34,35]. Sun et al. assert that GLP-1 amplifies anti-apoptotic signalling and reinstates metabolic resilience in insulin-resistant follicles via the phosphorylation-mediated silencing of FOXO1, thereby fostering granulosa cell proliferation in the ovaries of PCOS mice [18]. The findings of Saber et al. demonstrated considerable granulosa-cell death, follicular atresia, oxidative stress, and total inhibition of gonadotropin-dependent steroidogenesis in metabolically normal rats after prolonged liraglutide administration, which sharply contrasts with this profile [32]. Saber et al. propose that liraglutide may function as an ovarian toxin in physiological contexts, whereas Sun et al. characterise GLP-1RA signalling as a protective mechanism for metabolically dysregulated follicles [32].

Comparing the GLP-1–FOXO1 model by Sun et al. with the BMP–Smad modulation by Nishiyama et al. elucidates their distinctions more clearly [18,31]. Nishiyama's study demonstrates that incretin signalling, particularly GIP and, to a lesser extent, GLP-1, suppresses StAR, P450scc, and 3β-HSD, hence diminishing progesterone production while concurrently enhancing Smad1/5/8 phosphorylation in response to BMP-6 [31]. These results clearly contradict the findings of Sun et al., which revealed that GLP-1 promotes healthy follicular survival in PCOS via FOXO1-dependent anti-apoptotic mechanisms. This research outlines a molecular route via which GLP-1RA administration reduces FSH responsiveness and luteal differentiation. The comparison reveals that the metabolic environment of PCOS vs. normal ovary significantly affects the progression of GLP-1 signalling concerning granulosa cell fate and steroidogenesis.

Xiong et al. revealed that liraglutide and semaglutide modify the gut microbiota in mice with DHEA-induced PCOS [34]. They do this by increasing butyrate-producing taxa, restoring microbial diversity, and improving androgenic and metabolic indices, thereby confounding the process. This microbiota-mediated mechanism, in conjunction with FOXO1 signalling and BMP inhibition, introduces a third mechanistic dimension by suggesting that GLP-1 receptor agonists influence ovarian function via metabolic communication between the gut and the ovaries [39]. The study by Sun, Nishiyama, and Saber does not include this method [18,31,32]. Xiong's research indicates that the advantages of GLP-1RA in PCOS may derive from systemic metabolic reconfiguration driven by microbial metabolites, especially short-chain fatty acids that influence insulin sensitivity and inflammatory response, alongside direct ovarian impacts [34]. Yin et al. enhanced the mechanistic framework by investigating male reproductive tissues and finding that neither semaglutide nor liraglutide adversely affected testicular morphology, motility, or sperm count in elderly or diabetic mice [35]. Their findings provide a relevant comparison to the female-focused data reported by Saber et al., albeit concentrating on male reproductive physiology [32]. Gonadal toxicity is neither ubiquitous or unavoidable. It may be an ovarian-specific occurrence shaped by follicular physiology and sex-specific steroidogenic processes. In males, exposure to GLP-1 receptor agonists seems to be neutral and non-harmful, even under metabolic stress [35].

Compiling all mechanistic information reveals a consistent pattern: GLP-1 receptor agonists may disrupt normal ovarian function when administered to healthy animals over an extended duration [40]. Nevertheless, they often reinstate cellular function when metabolism is impaired in PCOS models. The metabolic improvements provided by microbiota, as shown by Xiong et al., together with the FOXO1-mediated anti-apoptotic effects observed by Sun et al., jointly confirm therapeutic benefits in PCOS biology [34]. The oxidative stress-induced follicular degeneration identified by Saber et al. and the progesterone suppression shown by Nishiyama et al. highlight concerns about the potential impact of GLP-1 receptor agonists on ovarian function in euglycemic, non-PCOS mice [31,32].

In contrast to the contradicting molecular and animal results, clinical research investigating the reproductive effects of GLP-1 receptor agonists in women with PCOS reveals a notably consistent pattern of benefit [41]. A consolidated clinical signal from clinical trials, meta-analyses, and narrative reviews indicates that GLP-1 receptor agonists routinely enhance metabolic dysfunction, menstrual regularity, ovulation, and, in several instances, spontaneous conception rates in overweight or obese individuals with polycystic ovary syndrome [42]. Despite this convergence, studies demonstrate considerable diversity in the strength, nature, and reproductive implications of these benefits, requiring a nuanced synthesis. The randomised trials by Salamun et al. and Liu et al. demonstrate significantly increased natural pregnancy rates in obese women with PCOS after short-term GLP-1RA medication, providing the most persuasive clinical evidence for reproductive benefit. Salamun et al. discovered that the combination of metformin and low-dose liraglutide resulted in an impressive 85.7% pregnancy rate per embryo transfer [28,29]. This was almost thrice more than the rate seen with metformin alone. This is consistent with, but also contrasts with, the results of Liu et al., who indicated that exenatide pretreatment more than quadrupled the incidence of natural conception in comparison to metformin monotherapy [29]. A comparison of these two studies indicates a significant pattern: weight reduction was comparable across groups in Salamun et al. and only partly informative in Liu et al., indicating that both liraglutide and exenatide provide reproductive improvements that cannot be solely attributed to weight loss.

Meta-analytic evidence from Zhou et al. and De Hollanda Morais et al. corroborates these results, indicating that GLP-1 receptor agonists substantially decrease BMI and central adiposity while improving monthly regularity, ovulation likelihood, SHBG levels, and free testosterone levels [37,43]. Zhou et al. could not detect a notable increase in IVF pregnancy rates within aggregated datasets [37]. They specifically noted that GLP-1RA medication improves natural pregnancy rates (RR 1.72), which is consistent with the individual results of Liu and Salamun [28,29]. This disparity underscores a critical comparative aspect: although Salamun et al. identified a notable IVF advantage, this effect may be contingent upon particular population characteristics (severe obesity, poor responders) or transient metabolic optimisation prior to IVF, which may not be consistently observed in larger, more heterogeneous samples utilised in meta-analyses [28]. Nylander et al.'s recent findings support the notion that GLP-1 receptor agonists alter ovarian physiology beyond just facilitating weight loss [30]. Nylander documented benefits in bleeding ratio, ovarian volume, SHBG, and free testosterone, while metabolic advantages were minimal compared to previous GLP-1RA studies [30]. In contrast to Salamun and Liu, Nylander's research highlights the possibility of a direct relationship between GLP-1 signalling and ovarian endocrine function, indicating that indicators of ovarian function (bleeding pattern, androgenic profile, and ovarian size) may improve even in the absence of significant weight loss [28,29,30].

Narrative and clinical reviews, such as those by Hoteit et al., Goldberg & Boots, and Varughese et al., provide more comprehensive interpretative frameworks [22,38,44]. These studies together demonstrate that GLP-1RAs address many pathophysiological mechanisms essential to PCOS, including insulin resistance, chronic inflammation, hypothalamic ovarian dysregulation, and metabolic dysfunction. In conjunction with Sun et al.'s mechanistic evidence on FOXO1-mediated survival and Xiong et al.'s microbiome-related benefits, Hoteit et al. contend that GLP-1 receptor agonists may have a "direct role" in ovarian morphology and the restoration of ovulation [18,22,34]. A synergy between direct ovarian signalling and metabolic correction is suggested by the discovery that, when these reviews are compared with individual clinical trials, doctors consistently report improvements in reproductive outcomes, regardless of the diversity in weight reduction. Varughese et al. and Goldberg & Boots emphasise the rising incidence of "Ozempic pregnancies," demonstrating that exposure to GLP-1RA before conception often results in spontaneous ovulation and unwanted births, despite a lack of official clinical evidence [38,44]. These signs, however anecdotal, support the concept that GLP-1RA medication may restore ovulatory function in women with PCOS who were previously anovulatory, consistent with the systematic findings provided by Salamun, Liu, and Zhou [28,29,37].

Evidence suggests that body mass index independently influences assisted reproduction results in women with PCOS, highlighting clinical heterogeneity. Su et al. found that pregnancy outcomes after blastocyst transfer varied significantly across BMI categories in PCOS patients receiving ultralong GnRH-a protocols, despite uniform diagnostic criteria and standardised treatment methods [45]. This discovery is especially important when assessing IVF results after GLP-1 receptor agonist pretreatment, since variations in reproductive success may be linked to improvements in metabolic condition rather than just to the diagnosis of PCOS.

Clinical research investigating the reproductive effects of GLP-1 receptor agonists in women with PCOS reveals a notably consistent pattern of benefit, in contrast to the more ambiguous mechanistic and animal evidence [46]. A consolidated clinical signal from clinical trials, meta-analyses, and narrative reviews indicates that GLP-1 receptor agonists consistently enhance metabolic dysfunction, menstrual regularity, ovulation, and, in many instances, natural conception rates in overweight or obese individuals with PCOS. Despite this convergence, research reveals considerable diversity in the nature, quantity, and reproductive implications of these advantages, requiring a nuanced synthesis [22,47].

The most persuasive clinical evidence for reproductive advantage comes from the randomised trials by Salamun et al. and Liu et al., both of which reveal significantly increased natural pregnancy rates in obese women with PCOS after short-term GLP-1RA medication [28,29]. Salamun et al. reported that the combination of metformin and low-dose liraglutide achieved an impressive 85.7% pregnancy rate per embryo transfer [28]. This risk was almost thrice greater than the rate associated with metformin alone. Liu et al. discovered that exenatide pretreatment more than quadrupled the natural conception rate in comparison to metformin monotherapy [29]. This resembles our findings; however, it is not identical. A significant pattern arises from the comparison of these two trials: weight decrease was comparable across the groups in Salamun et al. and only partly elucidated in Liu et al., indicating that both liraglutide and exenatide provide reproductive improvements that cannot be solely attributed to weight loss [28,29].

Meta-analytic evidence from Zhou et al. and De Hollanda Morais et al. corroborates these results, indicating that GLP-1 receptor agonists improve monthly regularity, increase the probability of ovulation, elevate SHBG levels, and decrease free testosterone, while markedly lowering BMI and central obesity [37,43]. Zhou et al. expressly indicated that GLP-1RA medication enhances natural pregnancy rates (RR 1.72), which is consistent with the individual results of Liu and Salamun [28,29,37]. However, they did not detect a significant increase in IVF pregnancy rates among aggregated datasets. This inconsistency underscores a critical comparative aspect: although Salamun et al. recognised a substantial IVF advantage, this effect may depend on particular population characteristics (severe obesity, poor responders) or short-term metabolic optimisation prior to IVF, which may not be consistently observable in larger, more heterogeneous samples employed in meta-analyses [28]. Nylander et al.'s recent results support the notion that GLP-1 receptor agonists alter ovarian function beyond just facilitating weight loss [30]. Nylander documented gains in bleeding ratio, ovarian volume, SHBG, and free testosterone, with only slight metabolic advancements compared to previous GLP-1RA studies [30]. In contrast to Salamun and Liu, Nylander's research highlights the possibility of a direct relationship between GLP-1 signalling and ovarian endocrine function, indicating that markers of ovarian function (including bleeding patterns, androgenic profiles, and ovarian size) may improve even without significant weight loss [28,29,30].

Narrative and clinical reviews, such as those by Hoteit et al., Goldberg & Boots, and Varughese et al., provide more extensive interpretative frameworks [22,38,44]. The reviews together suggest that GLP-1RAs target many pathophysiology components of PCOS, including metabolic dysfunction, insulin resistance, chronic inflammation, and hypothalamic-ovarian dysregulation. Hoteit et al. contend that GLP-1 receptor agonists may have a "direct role" in ovarian morphology and the restoration of ovulation, supporting the mechanistic results of Sun et al. regarding FOXO1-mediated survival and the microbiome-related advantages identified by Xiong et al. [18,22,34]. The observation that clinicians consistently report improvements in reproductive outcomes when these reviews are compared with individual clinical trials, regardless of variations in weight loss, suggests a synergistic relationship between direct ovarian signalling and metabolic correction. Despite the absence of official clinical data, Varughese et al. and Goldberg & Boots discuss the increasing incidence of "Ozempic pregnancies" [38,44]. Exposure to GLP-1RA before conception often results in spontaneous ovulation and unintended pregnancies. These signs, however anecdotal, support the systematic findings shown by Salamun, Liu, and Zhou, suggesting that GLP-1RA medication may restore ovulatory function in women with PCOS who were previously anovulatory [28,29,37].

Non-pharmacological metabolic interventions have demonstrated a disconnection between metabolic enhancement and reproductive results. A recent systematic review and meta-analysis by Turetta et al. found that ketogenic dietary interventions significantly improve weight, insulin sensitivity, and endocrine parameters in women with PCOS [48]. However, reproductive outcomes are still variable and depend on the phenotype. These results support findings with GLP-1 receptor agonists, indicating that metabolic normalisation alone does not consistently lead to improved ovarian response or fertility. They also show how important it is to have personalised treatment plans.

It is essential to recognise the discrepancies and partial inconsistencies between animal and human evidence regarding the reproductive effects of GLP-1 receptor agonists when examining the current information. Numerous animal investigations have shown that GLP-1RA administration may induce ovarian suppression, granulosa cell death, and increased oxidative stress. Clinical investigations including women with obesity or PCOS have consistently shown metabolic and reproductive advantages.

The observed variances are likely attributable to fundamental variations in ovarian physiology between species, their baseline metabolic conditions, the administration methods of the dosages, and the duration of exposure. Animal studies sometimes use prolonged treatment periods or supraphysiological dosages, which may not adequately represent therapeutic applications in humans. Furthermore, human research often concentrates on insulin-resistant or obese populations, where GLP-1 signalling may have protective rather than inhibitory effects on ovarian function, whereas experimental models frequently use metabolically healthy animals. Therefore, the straight application of animal safety findings to human reproductive medicine requires prudence. Animal research raises significant mechanistic and toxicological issues. Ιt should be seen as hypothesis-generating rather than conclusive proof of human reproductive danger. Comprehending dose-dependent effects, treatment timing, and reproductive safety across many metabolic profiles necessitates well-conducted, long-term human investigations.

The safety profile of GLP-1RAs in reproductive situations is little clarified, despite their notable therapeutic benefits in obese women with PCOS. A notable pattern reveals that efficacy and risk are highly context-dependent, influenced by metabolic phenotype, timing of drug exposure, dosage, and the physiological state of the ovary and endometrium, when juxtaposing reproductive safety data from human trials with animal studies and mechanistic in vitro research [43,49]. Saber et al.'s preclinical research indicated that extended exposure to liraglutide causes considerable ovarian damage in metabolically normal rats, marked by granulosa cell apoptosis, follicular atresia, vacuolar degeneration, and significant oxidative stress, thereby raising serious safety concerns [32]. These data highlight that ovarian response is affected by metabolic state, markedly differing from the beneficial granulosa-cell survival effects reported by Sun et al. in PCOS mouse models [18]. In healthy ovaries, GLP-1 receptor agonists may suppress gonadotropin-dependent steroidogenesis [50]. However, in metabolically compromised PCOS tissue, as demonstrated by Sun, the same pathway enhances functionality, as indicated by Saber's findings of diminished FSH, LH, oestradiol, and progesterone levels, coupled with increased testosterone [18,32]. This disparity indicates a significant knowledge gap: The ovarian safety of GLP-1RA in normal-weight, non-PCOS women of reproductive age in humans is essentially uncharacterized.

Nishiyama et al.'s mechanistic study raises more questions about the functioning of the luteal phase [31]. Their in vitro study demonstrates that incretins inhibit progesterone production by augmenting the BMP Smad1/5/8 signalling pathway and down-regulating StAR, P450scc, and 3β-HSD. In some cases, these molecular abnormalities may hinder luteal competency or implantation. The mechanistic data clarify a biologically plausible pathway through which peri-ovulatory or pre-luteal GLP-1RA exposure may affect steroidogenesis, a gap frequently highlighted by endometrial researchers, despite the lack of human clinical trials showing progesterone deficiency during GLP-1RA administration. Sola-Leyva et al. emphasise a critical aspect, noting that the impact of GLP-1 receptor agonists on endometrial receptivity and implantation is mostly unclear [46]. The endometrium's reaction has not been examined in controlled human studies, in contrast to the metabolic effects on the ovaries. Sola-Leyva contends that modified decidualisation, stromal cell signalling, immune cell recruitment, and early implantation biology are areas of considerable molecular sensitivity where the impacts of GLP-1RA may be either neutral or adverse [46]. No research has differentiated the effects of the endometrium from those of the ovaries and metabolism. Nevertheless, the increased IVF pregnancy rates seen in the Salamun et al. study may indicate improved endometrial receptivity after metabolic augmentation. Thus, it is unclear whether GLP-1RAs have a direct effect on the human endometrium [28].

Comprehensive safety studies in clinical reviews elucidate the ambiguity further. Varughese et al. and Goldberg & Boots both indicate that an increasing number of women of reproductive age are being exposed to GLP-1 receptor agonists in real-world scenarios, sometimes referred to as "Ozempic pregnancies" [38,44]. Such exposures often result in unplanned births soon after the initiation of therapy. No teratogenic effects in humans are documented. Manufacturers advise ceasing medication at least one to two months before conception, owing to the lack of controlled research on prenatal exposure to evaluate safety during early embryogenesis [51]. Varughese et al. highlight a significant translational gap, since the majority of evidence about foetal safety is derived from animal toxicity studies conducted at levels too high for humans [38]. Research by Nylander and Zhou demonstrates that overweight women with PCOS do not exhibit cycle suppression or luteal irregularities, offering confidence to reproductive endocrinologists that medication improves menstrual regularity and ovarian function [30,37]. Yin et al.'s study on male reproduction indicates that GLP-1 receptor agonists do not adversely affect gonadal function in either gender [35]. Even at high dosages, they do not adversely affect sperm parameters. However, these results do not apply to women experiencing early embryo implantation or to healthy, thin women.

The independent and combined effects of polycystic ovarian syndrome and obesity on reproductive dysfunction provide a notable source of variability that requires further investigation. Recent clinical data suggest that obesity and PCOS are separate pathological disorders that uniquely affect metabolic, endocrine, and ovarian characteristics, rather than forming a solitary, cohesive phenotype. Vale-Fernandes et al. contend that both PCOS and body weight adversely influence fertility treatment results, while their interaction further diminishes reproductive success [52]. These results highlight the need for a customised paradigm in evaluating the reproductive effects of GLP-1 receptor agonists, suggesting that metabolic state and inherent ovarian disease should be assessed independently when analysing reproductive outcomes.

The influence of GLP-1 receptor agonists on luteal function, endometrial receptivity, ovarian activity, and metabolism is a significant unsolved matter in reproductive medicine. Despite evidence that pretreatment with GLP-1RA enhances conception and implantation rates, particularly in women with PCOS, the underlying mechanisms for these advantages remain unclear. The reason remains ambiguous, whether due to direct impacts on the endometrium, indirect metabolic alterations, or enhanced oocyte and embryo competence. Mechanistic facts on luteal steroidogenesis need more substantial investigations. In vitro data suggests that the manipulation of the FSH-cAMP and BMP- Smad pathways may suppress progesterone production; this phenomenon has not been well investigated in people. This indicates that luteal adequacy may be affected by exposure to GLP-1 receptor agonists during the periovulatory or luteal phase.

Therefore, future studies should focus on the direct evaluation of endometrial receptivity, including timed endometrial biopsies with transcriptomic and proteomic analysis, assessment of decidualisation markers, immune cell composition, and signalling pathways related to implantation. Clinical investigations investigating luteal hormone dynamics, implantation rates, and early pregnancy outcomes after controlled GLP-1RA administration are crucial for evaluating safety, timing, and reproductive consequences. To safely and rationally include GLP-1 receptor agonists into reproductive therapy protocols, these deficiencies must be addressed.

The information combined reveals many substantial safety issues and unsolved enquiries about the use of GLP-1 receptor agonists in reproduction. The reproductive safety of GLP-1 receptor agonists in metabolically healthy, normal-weight women is mainly unexplored, since existing human clinical data mostly concentrate on women with obesity or polycystic ovary syndrome. Secondly, interspecies differences and non-physiological dose limit the translational relevance of preclinical animal studies that raise concerns about ovarian suppression, oxidative stress, and altered steroidogenesis due to prolonged or heightened exposure. The impact of GLP-1 receptor agonists on human endometrial receptivity, luteal function, and early implantation has not been well assessed. Ultimately, it is unclear when, for how long, and to what degree GLP-1RA medication should be used in relation to ovarian stimulation and conception. These limitations highlight the need for carefully structured, phenotype-specific clinical studies before approving the widespread use of GLP-1 receptor agonists in reproductive medicine.

The substantial therapeutic promise of GLP-1 receptor agonists in reproductive medicine, especially for obese women with PCOS, is highlighted by the amalgamation of clinical, molecular, and animal data. However, the inconsistent results between preclinical and human studies highlight the need for focused translational research that explains molecular pathways pertinent to ovarian and endometrial physiology, identifies risk groups, and specifies therapy parameters.

It is essential to establish extensive, multicenter randomised studies to evaluate GLP-1 receptor agonists in women undergoing reproductive therapy. The current studies are constrained by modest sample sizes, brief treatment durations, and diverse reproductive outcomes. Research by Salamun, Liu, Nylander, and the meta-analysis by Zhou and De Hollanda Morais consistently demonstrate improvements in ovulation, menstrual regularity, natural conception rates, and, in some cases, IVF results [28,30,37,43]. To provide meaningful cross-study comparisons, next clinical research must use defined reproductive outcomes, including oocyte quality, ovulation rates, luteal adequacy, endometrial thickness and morphology, implantation rate, biochemical pregnancy, clinical pregnancy, and live birth rates. Furthermore, as shown by Salamun, procedures assessing short-term, preconception GLP-1RA exposure prior to IVF cycles require comprehensive validation, as they may function as an efficacious metabolic-priming technique to improve ovarian response and endometrial receptivity [28].

A secondary translational goal is the methodical investigation of endometrial effects, which Sola-Leyva et al. have consistently identified as a significant knowledge need [46]. Despite therapeutic studies routinely showing enhanced reproductive results, none have shown whether GLP-1RA signalling directly affects the endometrium. Molecular studies must assess decidualisation markers, endometrial stromal cell responses, immune cell recruitment, cytokine expression, and genes associated with implantation (LIF, integrins, cytokines, HOXA10, IGFBP1). We can ascertain whether GLP-1RAs exert neutral, positive, or detrimental effects on the implantation cascade only using biopsy-derived or organoid-based models. Nishiyama's mechanistic signals revealed incretin-mediated suppression of progesterone production, a pathway with considerable ramifications for luteal function and endometrial receptivity, highlighting the significance of this discovery [31].

Another method to interpret the data is to elucidate the dose-response and metabolic-context dependence in animal and in vitro research. The detrimental oxidative stress and follicular degeneration identified by Saber et al. in healthy rats starkly contrast with the protective benefits conferred by FOXO1 phosphorylation shown by Sun et al. in PCOS models [18,32]. Future research should examine the effects of insulin resistance, obesity, inflammation, and oxidative stress on ovarian responses to GLP-1 receptor agonists. Ovary-on-a-chip models, ex vivo follicular cultures, and human in vitro studies employing granulosa cells from both PCOS and non-PCOS patients could clarify whether the clinically observed ovarian benefits are dependent on metabolic disruption or if GLP-1RAs affect ovarian physiology independently of systemic metabolic conditions.

Subsequent research should examine the gut ovary axis as a mechanistic element contributing to the reproductive benefits associated with GLP-1 receptor agonists, in light of recent discoveries by Xiong et al. on gut microbiota modulation [34]. Assessments of short-chain fatty acids, metagenomic analysis, and investigations of faecal transplantation may clarify if modifications in microbiota have a causal role in linking GLP-1RA medication to enhanced ovulation, decreased testosterone levels, and rejuvenated follicular function. The microbiota results may indicate potential synergistic reproductive benefits of combining GLP-1 receptor agonists with dietary, probiotic, or metabolic-targeting treatments.

Varughese, Goldberg, and Sola-Leyva have emphasised that the long-term safety for the unborn and periconception is a critical area of translational significance that requires more investigation [38,44,46]. There is an urgent need for regulated pregnancy-exposure registries because to the rise in real exposure, often known as "Ozempic pregnancies." These should record foetal growth, placental morphology, early embryonic developmental outcomes, neonatal metabolic health, and long-term developmental trajectories in children conceived during or soon after GLP-1RA exposure. The periconceptional window is very sensitive and requires comprehensive examination because of the endocrine and implantation-related biochemical pathways involved.

The development of next-generation GLP-1-based therapies introduces a promising new domain of study. Multireceptor incretin agonists (GLP-1/GIP dual agonists, GLP-1/GIP/glucagon triagonists) may provide greater metabolic improvements relative to liraglutide or semaglutide, thereby increasing reproductive results. Nonetheless, they may have unique ovarian effects and more complex pathways. Translational research must emphasise comparative assessments of ovarian steroidogenesis, follicular dynamics, and endometrial function in PCOS models, paving the way for future clinical trials.

These translational goals combined indicate a growing recognition that GLP-1 receptor agonists serve as systemic metabolic regulators with significant reproductive implications, beyond their function as weight-loss medicines. Robust mechanistic and clinical research is crucial to define the ideal function of these drugs in augmenting fertility, boosting IVF results, and ensuring safe conception, especially as their use among women of reproductive age increases fast. In the next decade, we will ascertain if GLP-1 receptor agonists are exclusively beneficial for certain metabolic abnormalities, such as PCOS, or whether they will be integrated as a standard approach to enhancing reproductive health.