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Current IssueSpecial IssueEditorial BoardOnline First ArticlesArchive

Review Article

The Evolving Landscape of PCOS- Integrative Animal Models for a Complex Clinical Challenge: A Review

S
Sulagna Dash Mohapatra1
S
Sanjay Kumar Raul1,*
0000-0003-1886-1856
V
Vinita Dheeran2
1Department of Biotechnology, Rama Devi Women’s University, Bhubaneswar-751 022, Odisha, India.
2M.M.H College, Ghaziabad-201 009, Uttar Pradesh, India.

ABSTRACT

Polycystic ovary syndrome (PCOS) is a widespread endocrine disorder characterized by high level of androgen, unsuccessful ovulation, development of several cysts within the ovaries and related metabolic problems. The relevance of existing animal models in real-life contexts remains limited in the view of detailed studies. This review critically evaluates available PCOS constructs as they reproduce some of the attributes such as hyperandrogenism or insulin resistance but are unable to provide a comprehensive representation of the diversity of the condition, such as lean and non-hyperandrogenic phenotypes. Moreover, many of the models do not take into account developmental stages, long-term outcomes or effects of neuroendocrine and immune mechanisms. The current technological achievements indicate the possible ways out of these limitations. A comprehensive literature search was conducted using prominent biological and medical search engines, including PubMed, Scopus, Web of Science and Google Scholar which primarily focuses on studies, detailing animal models of PCOS. CRISPR gene editing technology, transplantation of gut microbiota, organ-on-chip technology and humanized xenograft models offer opportunities to develop systems that can be precisely applied to real-life situations. Integrative advanced model is essential in detecting biological influences, such as hormonal, metabolic, immunological, neuroendocrine and environmental factors, at various stages in life. Advanced models will further increase the understanding of the pathophysiology of PCOS and the evaluation of novel interventions, including insulin sensitizers, microbiota modulators, anti-inflammatory drugs, hormonal therapies and anti-androgens. This review represents a systematic initiative to improve animal model techniques that can hasten translational research innovations and enhance mechanistic understanding and treatment of PCOS.

INTRODUCTION

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting majority of the reproductive aged women. About 6-13% women of reproductive age are affected by this condition, with up to 70% of cases remaining undiagnosed (WHO, 2025). However, with emergence of clinical and molecular evidences, PCOS is now recognized as a multisystem gynaecological condition. It includes metabolic, endocrine, immunological and psychological aspects that change throughout a woman’s life. It starts with exposures during foetal life, continuing through adolescence, adulthood and postmenopausal phases. The multifactorial etiopathogenesis of PCOS is highlighted by contemporary research. It implicates a complex interplay of hyperandrogenism, insulin resistance, chronic low-grade inflammation, hypothalamic-pituitary-ovarian (HPO) axis dysregulation, oxidative stress, gut microbiota dysbiosis and epigenetic changes. These factors interact at both systemic and tissue-specific levels such as ovary, hypothalamus, adipose tissue, pancreas and liver, which eventually leads to its heterogeneity. The primary reproductive symptoms experienced by PCOS patients are menstrual irregularities and infertility, while some women experienced metabolic complications including obesity, dyslipidaemia, impaired glucose tolerance and type 2 diabetes mellitus (T2DM) (Lim et al., 2013). The phenotype manifestation of PCOS affected by race, age, environmental exposure and lifestyle choices which are again responsible for the diversity of symptoms. However, with the advancement of research and technology, PCOS is now recognized as a dynamic spectrum disorder which requires precision in diagnosis, treatment and research modelling (Carmina and Lobo, 2004). This paradigm shift necessitates novel research development of animal models that can replicate the diverse clinical and genetic traits identified in PCOS.
       
To date, various animal models have been established by methods such as administration of pre- and postnatal androgen hormones (e.g., Dehydroepiandrosterone (DHEA), testosterone, dihydrotestosterone), insulin or high-fat diet models, letrozole models (an aromatase inhibitor) and genetic manipulation. This yielded valuable information regarding some characteristics of PCOS, such as ovulatory failure, arrested follicular development and hyperinsulinemia. However, the existing PCOS animal models also have major drawbacks. Most of these addressed isolated traits such as hyperandrogenism without simulating the complete picture of PCOS with its metabolic, inflammatory and neuroendocrine components (McCartney and Marshall, 2016). Non-hyperandrogenic types like Phenotype D, prevalent in certain groups, are seldom investigated and few of the models account for age-dependent progression or transgenerational transmission of the disease. Lean PCOS which is prevalent in South and East Asia defined by insulin resistance without obesity, is largely overlooked. Moreover, neuroendocrine factors including GnRH pulsatility, kisspeptin signalling and hypothalamic GABA tone are inadequately represented in models (Moore et al., 2013). These gaps not only restrict the knowledge of the genesis and course of the illness, but they also make it more difficult to develop and validate successful treatment plans, particularly when focused on the disorder’s immunological and metabolic components. In light of these limitations, this review aims to address the need for translational, integrative and comprehensive animal models that better capture the clinical variety and mechanistic complexity of PCOS in human beings. With a focus on a multi-hit strategy that integrates combinations of endocrine, metabolic, nutritional, inflammatory and developmental perturbations and analyses the advantages and disadvantages of existing animal models and suggests a new framework for “Next-generation PCOS modelling”.
       
A systematic search was performed at Rama Devi Women’s University, Bhubaneswar, Odisha, India to identify, examine and synthesise studies regarding the cause of the illness, model systems and their utility in medicine. Databases: PubMed, Scopus, Web of Science, Google Scholar, Embase, Science Direct, Springer Link and Wiley Online Library were used. The study conducted the search between January 2000 and May 2025 and have limited the search to the studies published after 2015 since this period includes the latest revelations. The position statements of professional organizations, such as the endocrine society, American society for reproductive medicine (ASRM), European society of human reproduction and embryology (ESHRE) and the world health organization (WHO) were searched. Detailed literature search strategy was established in order to address research articles that used animal models to explore pathophysiology of PCOS or therapeutic treatment. Articles eligible were original research, peer and systematic reviews taking animal models of any PCOS pathophysiology or intervention therapeutic process as the area of investigation. Clinical-only studies; case reports; commentaries; non-English contributions and studies without sufficiently detailed methodology were excluded. The combined study will provide the information and direction of designing the next generation animal models that are phenotypically correct, mechanistically sound and clinically applicable to propelling research on PCOS.
                                                          
Traditional animal models of PCOS
 
To better understand the underlying mechanisms of PCOS, researchers have long relied on conventional animal models that attempt to replicate its features, including disrupted ovulation, elevated androgen levels and cystic ovarian structures. These models typically involve pharmacological, hormonal, dietary, or genetic interventions that simulate aspects of the human disorder.
 
Androgen-induced models
 
Androgen-based models remain the most widely used due to the central role of hyperandrogenism in PCOS. Administration of exogenous androgens such as testosterone, dehydroepiandrosterone (DHEA), or dihydrotestosterone (DHT) in rodents induce hallmark PCOS features, including anovulation, cystic ovarian morphology and hyperandrogenic symptoms (Mallya et al., 2025). For instance, DHEA-treated mice develop enlarged ovaries with arrested follicles, mimicking the cystic pattern observed in human PCOS. Similarly, letrozole-induced models (via aromatase inhibition) lead to increased endogenous androgen levels and replicate both reproductive and metabolic traits including disrupted estrous cycles, insulin resistance and weight gain (Ebenezer et al., 2020). However, a key limitation of these models is their tendency to simulate an acute, drug-induced state rather than a chronically evolving syndrome. Moreover, they inadequately represent the developmental origins of PCOS, which are believed to involve prenatal androgen exposure and long-term programming effects (Kamada et al., 2022).
 
Estrogen and progesterone-based models
 
Less commonly used are models involving exogenous administration of estradiol valerate or chronic exposure to constant light, which disrupt the normal estrous cycle and induce ovarian changes. Although these models can cause anovulation that is chronic and polycystic-like ovaries, they don’t accurately mimic the endocrine disturbances occurring in human PCOS. Estrogen-dominant conditions do not accurately represent the hyperandrogenism and metabolic states observed in most PCOS patients. Therefore, the models are of limited usefulness and are mostly obsolete in PCOS research today (Oakley et al., 2011).
 
Genetic models
 
With the progress of molecular biology, scientists have developed genetically modified models to study how specific genes influence PCOS. Mice having either the targeted follicle-stimulating hormone receptor (FSHR), insulin signalling, or luteinizing hormone receptor (LHR) genes possess some PCOS characteristic. For example, when anti-Müllerian hormone (AMH) is abnormally elevated during fetal life, it mimics the prenatal programming theory of PCOS. Concurrently, human DENND1A mutations associated with androgen production in transgenic mice lead to ovulation dysfunction as well as increased androgen levels (Gao et al., 2016). Although these breakthroughs have been achieved, genetic models are time-consuming, expensive and typically do not mimic the entire PCOS syndrome. Moreover, most genetically modified animals lack the global metabolic derangements or inflammation found in human patients and hence limit their research utility (Biswas et al., 2021).
 
Diet-induced and environmental models
 
Environmental exposure such as that characterized by diet and endocrine disrupting chemicals (EDCs) have equally been employed to induce PCOS-like features in experimental animals. HFD models are designed to mimic the metabolic abnormality in PCOS obese women with insulin resistance, hyperinsulinemia and increased adiposity. These are especially valuable for researching metabolic-dominant PCOS phenotypes. In parallel, prenatal or perinatal exposure to EDCs such as bisphenol A (BPA) has been reported to cause permanent reproductive and metabolic alterations in the offspring, which is aligned with the developmental origins theory (Kelley et al., 2019; Alyasiri et al., 2024). However, these models often produce variable and inconsistent reproductive phenotypes and are heavily influenced by genetic background, diet composition and environmental housing conditions, which complicates reproducibility and interpretation (Rakic et al., 2023).
 
Cross-model limitations and gaps
 
Traditional PCOS models exhibit several critical limitations, especially in replicating the full spectrum of clinical manifestations seen in human patients. These models are generally categorized based on the etiological trigger used namely androgen administration, hormonal manipulation, genetic alterations, or environmental/dietary exposures. Each category offers unique insights but falls short in fully reproducing the reproductive, metabolic and neuroendocrine features of PCOS as a multifactorial syndrome (Corrie et al., 2021). Most rodent models lack a menstrual cycle, exhibit species-specific ovarian physiology and fail to mirror the neuroendocrine feedback mechanisms involving the hypothalamic-pituitary-ovarian axis (Kumar et al., 2022). Additionally, there exists disconnection between severity and duration of induced symptoms in animals compared to the chronic and lifelong course of PCOS. Larger animal models (e.g., sheep or primates) provide better physiological parallels but are associated with higher ethical concerns, logistical complexity and financial costs. Furthermore, ethnic-specific phenotypes, such as lean PCOS or non-hyperandrogenic variants, are poorly represented in current models, despite being clinically significant in human populations (Padmanabhan and Veiga-Lopez, 2013). The different traditional animal model used in PCOS research is described in Table 1.

Table 1: Traditional models used in PCOS research.


 
The need for modernized PCOS models
 
PCOS is now understood to be a multifactorial, systems-level syndrome that interferes with the endocrine, metabolic, immunological and neuroendocrine axes, rather than being a reproductive disorder. This increased awareness highlights the necessity for novel animal models of the complex pathophysiology of PCOS. More recently, new models embrace the developmental origins of health and disease (DOHaD) paradigm, which provides the hypothesis that intrauterine and early life environmental exposures such as maternal androgen excess, gestational diabetes, or nutritional imbalance have the capacity to epigenetically direct long-term susceptibility to disease (Parker et al., 2022).
       
In PCOS, dysregulation of the HPO axis is inextricably linked with insulin resistance, dysfunction of visceral adipose tissue, low-grade chronic inflammation, oxidative stress and dysfunction of the gut-brain axis. These systems are not separate from one another and models failing to account them are likely to oversimplify the syndrome. Further, recent findings have unveiled the contribution of the gut microbiome and neuroinflammation towards sustaining both metabolic and reproductive symptoms and models must incorporate multi-organ and systemic disease aspects (Senthilkumar and Arumugam, 2025).
       
Patient heterogeneity is another cause of complexity that necessitates more advanced preclinical modelling. PCOS phenotypes in the clinic range from obese, insulin-resistant women to lean, normoinsulinemic women who are defined by extreme reproductive dysfunction. Similarly, ethnic background significantly influences the expression of PCOS symptoms. South Asian women tend to present with early-onset, metabolically severe phenotypes, East Asians exhibit fewer signs of hyperandrogenism and African-American women display greater metabolic burden but relatively less hirsutism. Current animal models, predominantly based on western phenotypes, fail to represent this diversity. There is a growing consensus in the scientific community that stratified, phenotype-specific models are essential to ensure that preclinical findings are generalizable and applicable across global populations (Shi and Vine, 2012a,b).
       
The lack of fidelity in existing animal models has also contributed to the poor translational success of many pharmacological interventions for PCOS. Anti-androgens, insulin sensitizers (e.g., metformin, thiazolidinediones) and ovulation-inducing agents show variable efficacy in clinical settings and many drugs that perform well in preclinical trials fail to replicate their benefits in human patients. This discrepancy is often due to the failure of animal models to mimic the complex hormonal milieu, chronicity and multi-system involvement seen in PCOS. Also, rodent models lack crucial components of the human menstrual cycle. This makes it difficult to utilize the results on hormone feedback control and ovulation disorders (Bellofiore et al., 2021).
 
Emerging strategies in animal modelling of PCOS: Towards complex, human-relevant systems
 
Novel animal models have been developed due to the limitations of the classical PCOS models. The new models try to more closely replicate the syndrome’s complexity. They cover combinations of genetic, environmental, hormonal and microbial factors. Additionally, they encourage approaches involve multi-hit models, gene-editing technologies, transgenic models, humanized models and non-rodent models, each of them contributing unique insights into the complex biological characteristics of PCOS (Pei et al., 2023).
 
Multi-hit models
 
Multi-hit or combinatorial models are gaining increasing recognition as the optimal models to investigate PCOS. The models incorporate many risk factors such as prenatal exposure to androgen, postnatal high-fat diet, stress and endocrine disruptor exposure. They are employed to demonstrate the PCOS onset and its progression over time. For instance, experiments exposing mice to dihydrotestosterone (DHT) prenatally and a high-fat diet subsequently have replicated both reproductive dysfunction (such as inability to ovulate and polycystic ovary morphology) and metabolic dysfunction (such as insulin resistance and liver fat deposition), which are characteristics of typical phenotype A PCOS. Additionally, it exhibited long-term hypothalamic inflammation, impaired glucose metabolism and elevated androgen receptor expression hallmarks closely aligned with human PCOS pathology (Kamada et al., 2022).
 
CRISPR/Cas9 and targeted genome editing
 
Advancements in gene-editing technologies, particularly CRISPR/Cas9, have enabled the precise manipulation of genes implicated in PCOS. Researchers have introduced human single nucleotide polymorphisms (SNPs) into murine models to study gene-environment interactions in vivo. PCOS-linked genes (GWAS) such as AMH, FTO, INSR, DENND1A and TCF7L2 have been the subject of CRISPR editing. A study generated a mouse model that carries the AMH variant linked to PCOS, which exhibited hyperactivated LH pulsatility and delayed puberty. This model provided mechanistic information about neuroendocrine dysfunction and important for understanding possible genotype-specific responses to different environmental or therapeutic interventions (Ludovica et al., 2025).
 
Transgenic models with PCOS-specific hormonal profiles
 
Transgenic technologies have also been used to overexpress key hormonal regulators. These are anti-Müllerian hormone (AMH), gonadotropin-releasing hormone (GnRH) and androgen receptors (AR) in specific brain regions. Overexpression of AR in hypothalamic neurons has been shown to induce anovulation. It has also elevated LH levels and impaired insulin sensitivity in female mice mirroring PCOS phenotypes. More recently, GnRH neuron-specific overexpression of AR disrupts the HPO axis. It provides strong evidence for central contributions to PCOS pathogenesis (Watanabe et al., 2023).
 
Humanized mouse models
 
A humanized mouse model is an immunocompromised rodent hopped up with human tissue or even presented with patient biological samples. It is the latest in the pipeline of analysing the human-specific response to PCOS. By transplanting ovarian tissue of patients with PCOS in SCID mice, it is possible to monitor experimentally the processes of human folliculogenesis and stromal changes (Liu et al., 2024a,b). Moreover, inoculation of germ-free mouse with the gut microbiome of women with PCOS induced changes in metabolic phenotypes such as insulin resistance, elevated testosterone production and changed bile acid composition. Further, PCOS microbiota-transferred mice exhibited hypothalamic inflammation and increased AR expression, validating the gut-brain-ovary axis as a critical pathway in PCOS (Yang et al., 2024).
 
Non-rodent animal models
 
While rodent models dominate PCOS research, non-rodent species provide unique advantages, especially in mimicking human ovarian physiology, endocrine rhythms and placental structures. Non-human primates (e.g., rhesus macaques) are perhaps the most physiologically relevant, as prenatal androgen exposure in these animals induces hallmark PCOS features, including elevated LH, menstrual irregularities, hyperandrogenism and impaired glucose tolerance. A longitudinal study demonstrated that DHT-exposed rhesus females exhibited persistent ovarian stromal hyperplasia and metabolic syndrome into adulthood (Abbott et al., 2005, 2019). Sheep models, widely used in developmental programming studies, offer the benefit of large foetal size and hormonal monitoring over time. Prenatal testosterone-treated ewes develop reproductive and metabolic defects akin to human PCOS, including altered kisspeptin expression and adipose inflammation. Zebrafish, though evolutionarily distant, provide high-throughput, transparent models for screening PCOS drug candidates and studying steroidogenic gene regulation (Longkumer et al., 2022). A utilized CRISPR-edited zebrafish with cyp17a1 overexpression, showing disrupted follicle maturation and elevated testosterone levels (Li and Ge, 2020).
       
Together, these emerging strategies offer a multi-dimensional toolkit for modelling PCOS more accurately. By embracing combinatorial risk factors, developmental trajectories and species-specific insights, researchers can design next-generation models that not only improve mechanistic understanding but also bridge the gap between preclinical findings and human therapy (Lakshmi et al., 2025). Therefore, validation of the best model is essential for effective therapeutic efficacy. The next generation models used in PCOS research is described in Table 2 and overview of different animal model for PCOS is described in Fig 1.

Table 2: Next generation models used in PCOS research.



Fig 1: Overview of different animal model for PCOS.


 
Integration of advanced technologies in PCOS animal models: Enhancing translational relevance
 
The use of new and cutting-edge technology in animal modelling of PCOS has revolutionized the investigating and replicating nature of therapeutics. This spans across multi-omics platforms, computational modelling and optogenetics that gain information at a systems level about PCOS pathophysiology. Moreover, these enhances animal model outcomes agree with human clinical data, improving model fidelity and translation capability (Yang et al., 2022).
 
Multi-omics approaches for systems-level understanding
 
The multi-omics (Transcriptomics, proteomics and metabolomics) have emerged as essential technologies in solving the molecular puzzle of PCOS in the animal models. Transcriptomic studies, which are commonly performed with ovarian, hypothalamic or adipose tissue of rodents, provide PCOS-specific transcript levels related to inflammation-associated, steroidogenic, insulin-resistant and neuroendocrine-controlled pathways. Indeed, the recent RNA-seq data in the case of letrozole-induced PCOS mice demonstrated that Cyp17a1, TNF-alpha and Ar genes were upregulated, being a direct parallel of human PCOS transcriptomic signatures. Using mass spectrometry-based systems, it is possible to determine altered proteins in the serum or the follicular fluid with the help of proteomics. Study of DHT-treated mice has identified biomarkers of a molecular fingerprint of systemic dysregulation with elevated SHBG, reduced IGF-1 and altered levels of cytokines. The disrupted glucose metabolism and lipid metabolism, which is a hallmark of metabolic PCOS, could be explained with the help of metabolomics (Wang et al., 2022). The significant metabolites identified by researchers based on NMR and LC-MS that significantly alter in response to androgen and HFD exposure in mice are branched-chain amino acids, glycerophospholipids and bile acids, indicating more significant metabolic imbalance  (Zhang et al., 2023).
 
Neuroendocrine imaging and optogenetics
 
Since the key regulation of the reproductive hormones in PCOS requires accurate mapping of neuronal networks of the hypothalamus, this is imperative. Neuroendocrine imaging of real-time neuronal populations (through fiber photometry and in vivo calcium imaging) has been conducted in evidence to include kisspeptin, GnRH and dopaminergic neurons all of which have been shown to be dysregulated in PCOS. An experiment indicated that kisspeptin neurons of treated female mice with Letrozole were hyperactive, which was in line with a higher LH pulsatility (Esparza et al., 2020). Such functional studies have been improved further with optogenetics, which is the use of light to activate or suppress specific neurons. It has been established that excess androgen can rearrange hypothalamic feedback circuits when they have demonstrated abnormalities of LH secretion patterns in androgen proportions in optogenetic-activated magnacillin mice. Such tools make it possible to make precise adjustments in the reproductive pathways of experimental PCOS and provide an unrivalled level of insight into the neuroendocrine abnormalities (Chen et al., 2022).
 
Gut microbiota transplantation and the gut-brain-ovary axis
 
The gut microbiome plays a vital role in the etiology and sustenance of PCOS. The transfer of fecal microbiota from patients into germ-free mice resulted in transmission of PCOS-like traits, with hyperandrogenism, insulin resistance and disturbed estrous cycles (Hanna et al., 2025). One study found that these mice showed increased levels of gut-derived metabolites like short-chain fatty acids (SCFAs) and bile acids. These metabolites are known to regulate androgen production by liver and ovarian pathways. These observations bring up the gut-brain-ovary axis as a crucial point of intersection between endocrine and immune signals. Also, with respect to microbiota modulation of hypothalamic inflammation and AR expression, dysbiosis links become more visible between neuroendocrine disorders. These models thus become key for establishing microbiome-based therapies, such as probiotics, synbiotics and diet changes (O’Riordan et al., 2025; Putra et al., 2022).
 
AI-driven and in silico PCOS modelling
 
Artificial intelligence and computational modelling are altering PCOS research alongside pre-clinical experiments by developing in-silico models that simulate endocrine feedback systems. Such digital platforms incorporate complex omics data, hormone profiles of patients and results from animal models, thus assisting in constructing predictive models of disease progression and response to treatment (Upreti et al., 2025). The AI algorithms are fed data from CRISPR-edited models, neuroendocrine recording and metabolomics. They work to unearthing cryptic interactions and to finding drug targets. One such application is the use of digital twins, which are virtual replicas of animal or patient models, so that researchers run treatments in silico before real trials. These will lead to better hypothesis generation, a more refined experimental design and will alleviate the requirement for large animal groups by predicting the outcomes of hormonal or drug treatment (Moral et al., 2024).
 
Future prospective for advancing PCOS animal models
 
With the changing concept of PCOS, there is an urgent demand to update and standardize animal modelling approaches, to guarantee a translational relevance, reproducibility and scientific significance. Among all suggestions that arise out of the recent expert consensus and the studies, there is the need to create standardized protocols to induce the PCOS model, its phenotyping and validation. Presently, the differences in dose, duration of treatment and inclusion criteria of defining the types of PCOS in various studies cause some inconsistencies, which are an obstacle to comparative study. However, the same interventions, including PCOS induced by the use of letrozole, can have opposite outcomes depending on strain-of-mouse, age, or environmental conditions. The reproducibility would be improved by adoption of a standardized protocol with a defined cut-off of hyperandrogenism, ovulatory dysfunction, insulin resistance and ovarian morphology, making cross-laboratory validation possible (Stener-Victorin et al., 2020).
       
The other suggestion includes constructing central repositories and databases of animal models of PCOS, which preferably come under the jurisdiction of the National Institutes of Health (NIH), the Organization of Economic Co-operation and Development (OECD). Such platforms can contain the deposition of complete collections of metadata, phenotypic descriptions, omics data and image libraries to minimize redundancy and maximize transparency and speed of information exchange. The endocrine society provides the possible solution to this problem in the form of the PCOS model registry including design tools and algorithms matching phenotypes (Ryu et al., 2019).
               
The multifaceted etiology and multisystem expression of PCOS necessitate the cross-border collaboration of multiple medical specialties. The illness needs to be explained by a convergence of endocrinology, immunology, reproductive biology, systems biology and artificial intelligence (AI). In multi-omics research using machine-learning programmed PCOS rodents, AI-based analytics not only find biomarker indicators and treatment markings, but also facilitate the theoretical and phenotypic journeys of endocrine-metabolic systems (Verma et al., 2024).

CONCLUSION

PCOS is a complex disorder predetermined with endocrine, metabolic, neuroendocrine, immune, genetic and environmental imbalances. Over the years, though in practice useful, conventional experimental models tend to emphasize particular parameters whether hyperandrogenism or insulin resistance and ignore the wide heterogeneity which can occur in terms of ethnicity, geography and development. This constraint guided effects on therapeutic translation, show promise in preclinical studies and tends to have low efficacy in clinical studies. Recent research focuses more on multifactorial models indicating the complexity of the syndrome. Multi-hit designs, CRISPR/Cas9 gene editing, humanized mice and nonrodent hosts are becoming more and more common. Also, more recent methods like multi-omics platforms, optogenetics, neuroendocrine imaging, gut microbiota transplants and AI-based simulations can enable mapping disease mechanisms sequentially, enabling more specific and targeted therapies. In harmony with these scientific breakthroughs, ethical and regulatory considerations are diminishing animal research and growing expenditure on organoids, ovary-on-chip platforms and stem cell based in vitro infrastructure. Such developments are harmonized with global commitments to the philosophy of 3Rs and with the news paradigm of an age of post-animal research. Future PCOS research will necessitate interdisciplinary perspective, explicit standard models, increased data sharing and model tailoring to particular phenotypes and populations.  The synergistic approach to these efforts has a potential to provide novel diagnostics, precision therapy and mechanistic insights that, in the future, are capable of redefining the knowledge and management of PCOS in diverse patient subsets.

ACKNOWLEDGEMENT

We express our gratitude to Ms. Pyari Payal Beura and Ms. Shibani Jena of SKR laboratory for their unwavering assistance and valuable recommendations regarding many elements of our assessment.
 
Disclaimers
 
NA.
 
Funding
 
Ms. Sulagna Dash Mohapatra was financially supported by Department of Biotechnology, Ministry of Science and Technology, Government of India with Fellowship number DBT/2025-26/RDWU/2717.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

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    Review Article

    The Evolving Landscape of PCOS- Integrative Animal Models for a Complex Clinical Challenge: A Review

    S
    Sulagna Dash Mohapatra1
    S
    Sanjay Kumar Raul1,*
    0000-0003-1886-1856
    V
    Vinita Dheeran2
    1Department of Biotechnology, Rama Devi Women’s University, Bhubaneswar-751 022, Odisha, India.
    2M.M.H College, Ghaziabad-201 009, Uttar Pradesh, India.

    ABSTRACT

    Polycystic ovary syndrome (PCOS) is a widespread endocrine disorder characterized by high level of androgen, unsuccessful ovulation, development of several cysts within the ovaries and related metabolic problems. The relevance of existing animal models in real-life contexts remains limited in the view of detailed studies. This review critically evaluates available PCOS constructs as they reproduce some of the attributes such as hyperandrogenism or insulin resistance but are unable to provide a comprehensive representation of the diversity of the condition, such as lean and non-hyperandrogenic phenotypes. Moreover, many of the models do not take into account developmental stages, long-term outcomes or effects of neuroendocrine and immune mechanisms. The current technological achievements indicate the possible ways out of these limitations. A comprehensive literature search was conducted using prominent biological and medical search engines, including PubMed, Scopus, Web of Science and Google Scholar which primarily focuses on studies, detailing animal models of PCOS. CRISPR gene editing technology, transplantation of gut microbiota, organ-on-chip technology and humanized xenograft models offer opportunities to develop systems that can be precisely applied to real-life situations. Integrative advanced model is essential in detecting biological influences, such as hormonal, metabolic, immunological, neuroendocrine and environmental factors, at various stages in life. Advanced models will further increase the understanding of the pathophysiology of PCOS and the evaluation of novel interventions, including insulin sensitizers, microbiota modulators, anti-inflammatory drugs, hormonal therapies and anti-androgens. This review represents a systematic initiative to improve animal model techniques that can hasten translational research innovations and enhance mechanistic understanding and treatment of PCOS.

    INTRODUCTION

    Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting majority of the reproductive aged women. About 6-13% women of reproductive age are affected by this condition, with up to 70% of cases remaining undiagnosed (WHO, 2025). However, with emergence of clinical and molecular evidences, PCOS is now recognized as a multisystem gynaecological condition. It includes metabolic, endocrine, immunological and psychological aspects that change throughout a woman’s life. It starts with exposures during foetal life, continuing through adolescence, adulthood and postmenopausal phases. The multifactorial etiopathogenesis of PCOS is highlighted by contemporary research. It implicates a complex interplay of hyperandrogenism, insulin resistance, chronic low-grade inflammation, hypothalamic-pituitary-ovarian (HPO) axis dysregulation, oxidative stress, gut microbiota dysbiosis and epigenetic changes. These factors interact at both systemic and tissue-specific levels such as ovary, hypothalamus, adipose tissue, pancreas and liver, which eventually leads to its heterogeneity. The primary reproductive symptoms experienced by PCOS patients are menstrual irregularities and infertility, while some women experienced metabolic complications including obesity, dyslipidaemia, impaired glucose tolerance and type 2 diabetes mellitus (T2DM) (Lim et al., 2013). The phenotype manifestation of PCOS affected by race, age, environmental exposure and lifestyle choices which are again responsible for the diversity of symptoms. However, with the advancement of research and technology, PCOS is now recognized as a dynamic spectrum disorder which requires precision in diagnosis, treatment and research modelling (Carmina and Lobo, 2004). This paradigm shift necessitates novel research development of animal models that can replicate the diverse clinical and genetic traits identified in PCOS.
           
    To date, various animal models have been established by methods such as administration of pre- and postnatal androgen hormones (e.g., Dehydroepiandrosterone (DHEA), testosterone, dihydrotestosterone), insulin or high-fat diet models, letrozole models (an aromatase inhibitor) and genetic manipulation. This yielded valuable information regarding some characteristics of PCOS, such as ovulatory failure, arrested follicular development and hyperinsulinemia. However, the existing PCOS animal models also have major drawbacks. Most of these addressed isolated traits such as hyperandrogenism without simulating the complete picture of PCOS with its metabolic, inflammatory and neuroendocrine components (McCartney and Marshall, 2016). Non-hyperandrogenic types like Phenotype D, prevalent in certain groups, are seldom investigated and few of the models account for age-dependent progression or transgenerational transmission of the disease. Lean PCOS which is prevalent in South and East Asia defined by insulin resistance without obesity, is largely overlooked. Moreover, neuroendocrine factors including GnRH pulsatility, kisspeptin signalling and hypothalamic GABA tone are inadequately represented in models (Moore et al., 2013). These gaps not only restrict the knowledge of the genesis and course of the illness, but they also make it more difficult to develop and validate successful treatment plans, particularly when focused on the disorder’s immunological and metabolic components. In light of these limitations, this review aims to address the need for translational, integrative and comprehensive animal models that better capture the clinical variety and mechanistic complexity of PCOS in human beings. With a focus on a multi-hit strategy that integrates combinations of endocrine, metabolic, nutritional, inflammatory and developmental perturbations and analyses the advantages and disadvantages of existing animal models and suggests a new framework for “Next-generation PCOS modelling”.
           
    A systematic search was performed at Rama Devi Women’s University, Bhubaneswar, Odisha, India to identify, examine and synthesise studies regarding the cause of the illness, model systems and their utility in medicine. Databases: PubMed, Scopus, Web of Science, Google Scholar, Embase, Science Direct, Springer Link and Wiley Online Library were used. The study conducted the search between January 2000 and May 2025 and have limited the search to the studies published after 2015 since this period includes the latest revelations. The position statements of professional organizations, such as the endocrine society, American society for reproductive medicine (ASRM), European society of human reproduction and embryology (ESHRE) and the world health organization (WHO) were searched. Detailed literature search strategy was established in order to address research articles that used animal models to explore pathophysiology of PCOS or therapeutic treatment. Articles eligible were original research, peer and systematic reviews taking animal models of any PCOS pathophysiology or intervention therapeutic process as the area of investigation. Clinical-only studies; case reports; commentaries; non-English contributions and studies without sufficiently detailed methodology were excluded. The combined study will provide the information and direction of designing the next generation animal models that are phenotypically correct, mechanistically sound and clinically applicable to propelling research on PCOS.
                                                              
    Traditional animal models of PCOS
     
    To better understand the underlying mechanisms of PCOS, researchers have long relied on conventional animal models that attempt to replicate its features, including disrupted ovulation, elevated androgen levels and cystic ovarian structures. These models typically involve pharmacological, hormonal, dietary, or genetic interventions that simulate aspects of the human disorder.
     
    Androgen-induced models
     
    Androgen-based models remain the most widely used due to the central role of hyperandrogenism in PCOS. Administration of exogenous androgens such as testosterone, dehydroepiandrosterone (DHEA), or dihydrotestosterone (DHT) in rodents induce hallmark PCOS features, including anovulation, cystic ovarian morphology and hyperandrogenic symptoms (Mallya et al., 2025). For instance, DHEA-treated mice develop enlarged ovaries with arrested follicles, mimicking the cystic pattern observed in human PCOS. Similarly, letrozole-induced models (via aromatase inhibition) lead to increased endogenous androgen levels and replicate both reproductive and metabolic traits including disrupted estrous cycles, insulin resistance and weight gain (Ebenezer et al., 2020). However, a key limitation of these models is their tendency to simulate an acute, drug-induced state rather than a chronically evolving syndrome. Moreover, they inadequately represent the developmental origins of PCOS, which are believed to involve prenatal androgen exposure and long-term programming effects (Kamada et al., 2022).
     
    Estrogen and progesterone-based models
     
    Less commonly used are models involving exogenous administration of estradiol valerate or chronic exposure to constant light, which disrupt the normal estrous cycle and induce ovarian changes. Although these models can cause anovulation that is chronic and polycystic-like ovaries, they don’t accurately mimic the endocrine disturbances occurring in human PCOS. Estrogen-dominant conditions do not accurately represent the hyperandrogenism and metabolic states observed in most PCOS patients. Therefore, the models are of limited usefulness and are mostly obsolete in PCOS research today (Oakley et al., 2011).
     
    Genetic models
     
    With the progress of molecular biology, scientists have developed genetically modified models to study how specific genes influence PCOS. Mice having either the targeted follicle-stimulating hormone receptor (FSHR), insulin signalling, or luteinizing hormone receptor (LHR) genes possess some PCOS characteristic. For example, when anti-Müllerian hormone (AMH) is abnormally elevated during fetal life, it mimics the prenatal programming theory of PCOS. Concurrently, human DENND1A mutations associated with androgen production in transgenic mice lead to ovulation dysfunction as well as increased androgen levels (Gao et al., 2016). Although these breakthroughs have been achieved, genetic models are time-consuming, expensive and typically do not mimic the entire PCOS syndrome. Moreover, most genetically modified animals lack the global metabolic derangements or inflammation found in human patients and hence limit their research utility (Biswas et al., 2021).
     
    Diet-induced and environmental models
     
    Environmental exposure such as that characterized by diet and endocrine disrupting chemicals (EDCs) have equally been employed to induce PCOS-like features in experimental animals. HFD models are designed to mimic the metabolic abnormality in PCOS obese women with insulin resistance, hyperinsulinemia and increased adiposity. These are especially valuable for researching metabolic-dominant PCOS phenotypes. In parallel, prenatal or perinatal exposure to EDCs such as bisphenol A (BPA) has been reported to cause permanent reproductive and metabolic alterations in the offspring, which is aligned with the developmental origins theory (Kelley et al., 2019; Alyasiri et al., 2024). However, these models often produce variable and inconsistent reproductive phenotypes and are heavily influenced by genetic background, diet composition and environmental housing conditions, which complicates reproducibility and interpretation (Rakic et al., 2023).
     
    Cross-model limitations and gaps
     
    Traditional PCOS models exhibit several critical limitations, especially in replicating the full spectrum of clinical manifestations seen in human patients. These models are generally categorized based on the etiological trigger used namely androgen administration, hormonal manipulation, genetic alterations, or environmental/dietary exposures. Each category offers unique insights but falls short in fully reproducing the reproductive, metabolic and neuroendocrine features of PCOS as a multifactorial syndrome (Corrie et al., 2021). Most rodent models lack a menstrual cycle, exhibit species-specific ovarian physiology and fail to mirror the neuroendocrine feedback mechanisms involving the hypothalamic-pituitary-ovarian axis (Kumar et al., 2022). Additionally, there exists disconnection between severity and duration of induced symptoms in animals compared to the chronic and lifelong course of PCOS. Larger animal models (e.g., sheep or primates) provide better physiological parallels but are associated with higher ethical concerns, logistical complexity and financial costs. Furthermore, ethnic-specific phenotypes, such as lean PCOS or non-hyperandrogenic variants, are poorly represented in current models, despite being clinically significant in human populations (Padmanabhan and Veiga-Lopez, 2013). The different traditional animal model used in PCOS research is described in Table 1.

    Table 1: Traditional models used in PCOS research.


     
    The need for modernized PCOS models
     
    PCOS is now understood to be a multifactorial, systems-level syndrome that interferes with the endocrine, metabolic, immunological and neuroendocrine axes, rather than being a reproductive disorder. This increased awareness highlights the necessity for novel animal models of the complex pathophysiology of PCOS. More recently, new models embrace the developmental origins of health and disease (DOHaD) paradigm, which provides the hypothesis that intrauterine and early life environmental exposures such as maternal androgen excess, gestational diabetes, or nutritional imbalance have the capacity to epigenetically direct long-term susceptibility to disease (Parker et al., 2022).
           
    In PCOS, dysregulation of the HPO axis is inextricably linked with insulin resistance, dysfunction of visceral adipose tissue, low-grade chronic inflammation, oxidative stress and dysfunction of the gut-brain axis. These systems are not separate from one another and models failing to account them are likely to oversimplify the syndrome. Further, recent findings have unveiled the contribution of the gut microbiome and neuroinflammation towards sustaining both metabolic and reproductive symptoms and models must incorporate multi-organ and systemic disease aspects (Senthilkumar and Arumugam, 2025).
           
    Patient heterogeneity is another cause of complexity that necessitates more advanced preclinical modelling. PCOS phenotypes in the clinic range from obese, insulin-resistant women to lean, normoinsulinemic women who are defined by extreme reproductive dysfunction. Similarly, ethnic background significantly influences the expression of PCOS symptoms. South Asian women tend to present with early-onset, metabolically severe phenotypes, East Asians exhibit fewer signs of hyperandrogenism and African-American women display greater metabolic burden but relatively less hirsutism. Current animal models, predominantly based on western phenotypes, fail to represent this diversity. There is a growing consensus in the scientific community that stratified, phenotype-specific models are essential to ensure that preclinical findings are generalizable and applicable across global populations (Shi and Vine, 2012a,b).
           
    The lack of fidelity in existing animal models has also contributed to the poor translational success of many pharmacological interventions for PCOS. Anti-androgens, insulin sensitizers (e.g., metformin, thiazolidinediones) and ovulation-inducing agents show variable efficacy in clinical settings and many drugs that perform well in preclinical trials fail to replicate their benefits in human patients. This discrepancy is often due to the failure of animal models to mimic the complex hormonal milieu, chronicity and multi-system involvement seen in PCOS. Also, rodent models lack crucial components of the human menstrual cycle. This makes it difficult to utilize the results on hormone feedback control and ovulation disorders (Bellofiore et al., 2021).
     
    Emerging strategies in animal modelling of PCOS: Towards complex, human-relevant systems
     
    Novel animal models have been developed due to the limitations of the classical PCOS models. The new models try to more closely replicate the syndrome’s complexity. They cover combinations of genetic, environmental, hormonal and microbial factors. Additionally, they encourage approaches involve multi-hit models, gene-editing technologies, transgenic models, humanized models and non-rodent models, each of them contributing unique insights into the complex biological characteristics of PCOS (Pei et al., 2023).
     
    Multi-hit models
     
    Multi-hit or combinatorial models are gaining increasing recognition as the optimal models to investigate PCOS. The models incorporate many risk factors such as prenatal exposure to androgen, postnatal high-fat diet, stress and endocrine disruptor exposure. They are employed to demonstrate the PCOS onset and its progression over time. For instance, experiments exposing mice to dihydrotestosterone (DHT) prenatally and a high-fat diet subsequently have replicated both reproductive dysfunction (such as inability to ovulate and polycystic ovary morphology) and metabolic dysfunction (such as insulin resistance and liver fat deposition), which are characteristics of typical phenotype A PCOS. Additionally, it exhibited long-term hypothalamic inflammation, impaired glucose metabolism and elevated androgen receptor expression hallmarks closely aligned with human PCOS pathology (Kamada et al., 2022).
     
    CRISPR/Cas9 and targeted genome editing
     
    Advancements in gene-editing technologies, particularly CRISPR/Cas9, have enabled the precise manipulation of genes implicated in PCOS. Researchers have introduced human single nucleotide polymorphisms (SNPs) into murine models to study gene-environment interactions in vivo. PCOS-linked genes (GWAS) such as AMH, FTO, INSR, DENND1A and TCF7L2 have been the subject of CRISPR editing. A study generated a mouse model that carries the AMH variant linked to PCOS, which exhibited hyperactivated LH pulsatility and delayed puberty. This model provided mechanistic information about neuroendocrine dysfunction and important for understanding possible genotype-specific responses to different environmental or therapeutic interventions (Ludovica et al., 2025).
     
    Transgenic models with PCOS-specific hormonal profiles
     
    Transgenic technologies have also been used to overexpress key hormonal regulators. These are anti-Müllerian hormone (AMH), gonadotropin-releasing hormone (GnRH) and androgen receptors (AR) in specific brain regions. Overexpression of AR in hypothalamic neurons has been shown to induce anovulation. It has also elevated LH levels and impaired insulin sensitivity in female mice mirroring PCOS phenotypes. More recently, GnRH neuron-specific overexpression of AR disrupts the HPO axis. It provides strong evidence for central contributions to PCOS pathogenesis (Watanabe et al., 2023).
     
    Humanized mouse models
     
    A humanized mouse model is an immunocompromised rodent hopped up with human tissue or even presented with patient biological samples. It is the latest in the pipeline of analysing the human-specific response to PCOS. By transplanting ovarian tissue of patients with PCOS in SCID mice, it is possible to monitor experimentally the processes of human folliculogenesis and stromal changes (Liu et al., 2024a,b). Moreover, inoculation of germ-free mouse with the gut microbiome of women with PCOS induced changes in metabolic phenotypes such as insulin resistance, elevated testosterone production and changed bile acid composition. Further, PCOS microbiota-transferred mice exhibited hypothalamic inflammation and increased AR expression, validating the gut-brain-ovary axis as a critical pathway in PCOS (Yang et al., 2024).
     
    Non-rodent animal models
     
    While rodent models dominate PCOS research, non-rodent species provide unique advantages, especially in mimicking human ovarian physiology, endocrine rhythms and placental structures. Non-human primates (e.g., rhesus macaques) are perhaps the most physiologically relevant, as prenatal androgen exposure in these animals induces hallmark PCOS features, including elevated LH, menstrual irregularities, hyperandrogenism and impaired glucose tolerance. A longitudinal study demonstrated that DHT-exposed rhesus females exhibited persistent ovarian stromal hyperplasia and metabolic syndrome into adulthood (Abbott et al., 2005, 2019). Sheep models, widely used in developmental programming studies, offer the benefit of large foetal size and hormonal monitoring over time. Prenatal testosterone-treated ewes develop reproductive and metabolic defects akin to human PCOS, including altered kisspeptin expression and adipose inflammation. Zebrafish, though evolutionarily distant, provide high-throughput, transparent models for screening PCOS drug candidates and studying steroidogenic gene regulation (Longkumer et al., 2022). A utilized CRISPR-edited zebrafish with cyp17a1 overexpression, showing disrupted follicle maturation and elevated testosterone levels (Li and Ge, 2020).
           
    Together, these emerging strategies offer a multi-dimensional toolkit for modelling PCOS more accurately. By embracing combinatorial risk factors, developmental trajectories and species-specific insights, researchers can design next-generation models that not only improve mechanistic understanding but also bridge the gap between preclinical findings and human therapy (Lakshmi et al., 2025). Therefore, validation of the best model is essential for effective therapeutic efficacy. The next generation models used in PCOS research is described in Table 2 and overview of different animal model for PCOS is described in Fig 1.

    Table 2: Next generation models used in PCOS research.



    Fig 1: Overview of different animal model for PCOS.


     
    Integration of advanced technologies in PCOS animal models: Enhancing translational relevance
     
    The use of new and cutting-edge technology in animal modelling of PCOS has revolutionized the investigating and replicating nature of therapeutics. This spans across multi-omics platforms, computational modelling and optogenetics that gain information at a systems level about PCOS pathophysiology. Moreover, these enhances animal model outcomes agree with human clinical data, improving model fidelity and translation capability (Yang et al., 2022).
     
    Multi-omics approaches for systems-level understanding
     
    The multi-omics (Transcriptomics, proteomics and metabolomics) have emerged as essential technologies in solving the molecular puzzle of PCOS in the animal models. Transcriptomic studies, which are commonly performed with ovarian, hypothalamic or adipose tissue of rodents, provide PCOS-specific transcript levels related to inflammation-associated, steroidogenic, insulin-resistant and neuroendocrine-controlled pathways. Indeed, the recent RNA-seq data in the case of letrozole-induced PCOS mice demonstrated that Cyp17a1, TNF-alpha and Ar genes were upregulated, being a direct parallel of human PCOS transcriptomic signatures. Using mass spectrometry-based systems, it is possible to determine altered proteins in the serum or the follicular fluid with the help of proteomics. Study of DHT-treated mice has identified biomarkers of a molecular fingerprint of systemic dysregulation with elevated SHBG, reduced IGF-1 and altered levels of cytokines. The disrupted glucose metabolism and lipid metabolism, which is a hallmark of metabolic PCOS, could be explained with the help of metabolomics (Wang et al., 2022). The significant metabolites identified by researchers based on NMR and LC-MS that significantly alter in response to androgen and HFD exposure in mice are branched-chain amino acids, glycerophospholipids and bile acids, indicating more significant metabolic imbalance  (Zhang et al., 2023).
     
    Neuroendocrine imaging and optogenetics
     
    Since the key regulation of the reproductive hormones in PCOS requires accurate mapping of neuronal networks of the hypothalamus, this is imperative. Neuroendocrine imaging of real-time neuronal populations (through fiber photometry and in vivo calcium imaging) has been conducted in evidence to include kisspeptin, GnRH and dopaminergic neurons all of which have been shown to be dysregulated in PCOS. An experiment indicated that kisspeptin neurons of treated female mice with Letrozole were hyperactive, which was in line with a higher LH pulsatility (Esparza et al., 2020). Such functional studies have been improved further with optogenetics, which is the use of light to activate or suppress specific neurons. It has been established that excess androgen can rearrange hypothalamic feedback circuits when they have demonstrated abnormalities of LH secretion patterns in androgen proportions in optogenetic-activated magnacillin mice. Such tools make it possible to make precise adjustments in the reproductive pathways of experimental PCOS and provide an unrivalled level of insight into the neuroendocrine abnormalities (Chen et al., 2022).
     
    Gut microbiota transplantation and the gut-brain-ovary axis
     
    The gut microbiome plays a vital role in the etiology and sustenance of PCOS. The transfer of fecal microbiota from patients into germ-free mice resulted in transmission of PCOS-like traits, with hyperandrogenism, insulin resistance and disturbed estrous cycles (Hanna et al., 2025). One study found that these mice showed increased levels of gut-derived metabolites like short-chain fatty acids (SCFAs) and bile acids. These metabolites are known to regulate androgen production by liver and ovarian pathways. These observations bring up the gut-brain-ovary axis as a crucial point of intersection between endocrine and immune signals. Also, with respect to microbiota modulation of hypothalamic inflammation and AR expression, dysbiosis links become more visible between neuroendocrine disorders. These models thus become key for establishing microbiome-based therapies, such as probiotics, synbiotics and diet changes (O’Riordan et al., 2025; Putra et al., 2022).
     
    AI-driven and in silico PCOS modelling
     
    Artificial intelligence and computational modelling are altering PCOS research alongside pre-clinical experiments by developing in-silico models that simulate endocrine feedback systems. Such digital platforms incorporate complex omics data, hormone profiles of patients and results from animal models, thus assisting in constructing predictive models of disease progression and response to treatment (Upreti et al., 2025). The AI algorithms are fed data from CRISPR-edited models, neuroendocrine recording and metabolomics. They work to unearthing cryptic interactions and to finding drug targets. One such application is the use of digital twins, which are virtual replicas of animal or patient models, so that researchers run treatments in silico before real trials. These will lead to better hypothesis generation, a more refined experimental design and will alleviate the requirement for large animal groups by predicting the outcomes of hormonal or drug treatment (Moral et al., 2024).
     
    Future prospective for advancing PCOS animal models
     
    With the changing concept of PCOS, there is an urgent demand to update and standardize animal modelling approaches, to guarantee a translational relevance, reproducibility and scientific significance. Among all suggestions that arise out of the recent expert consensus and the studies, there is the need to create standardized protocols to induce the PCOS model, its phenotyping and validation. Presently, the differences in dose, duration of treatment and inclusion criteria of defining the types of PCOS in various studies cause some inconsistencies, which are an obstacle to comparative study. However, the same interventions, including PCOS induced by the use of letrozole, can have opposite outcomes depending on strain-of-mouse, age, or environmental conditions. The reproducibility would be improved by adoption of a standardized protocol with a defined cut-off of hyperandrogenism, ovulatory dysfunction, insulin resistance and ovarian morphology, making cross-laboratory validation possible (Stener-Victorin et al., 2020).
           
    The other suggestion includes constructing central repositories and databases of animal models of PCOS, which preferably come under the jurisdiction of the National Institutes of Health (NIH), the Organization of Economic Co-operation and Development (OECD). Such platforms can contain the deposition of complete collections of metadata, phenotypic descriptions, omics data and image libraries to minimize redundancy and maximize transparency and speed of information exchange. The endocrine society provides the possible solution to this problem in the form of the PCOS model registry including design tools and algorithms matching phenotypes (Ryu et al., 2019).
                   
    The multifaceted etiology and multisystem expression of PCOS necessitate the cross-border collaboration of multiple medical specialties. The illness needs to be explained by a convergence of endocrinology, immunology, reproductive biology, systems biology and artificial intelligence (AI). In multi-omics research using machine-learning programmed PCOS rodents, AI-based analytics not only find biomarker indicators and treatment markings, but also facilitate the theoretical and phenotypic journeys of endocrine-metabolic systems (Verma et al., 2024).

    CONCLUSION

    PCOS is a complex disorder predetermined with endocrine, metabolic, neuroendocrine, immune, genetic and environmental imbalances. Over the years, though in practice useful, conventional experimental models tend to emphasize particular parameters whether hyperandrogenism or insulin resistance and ignore the wide heterogeneity which can occur in terms of ethnicity, geography and development. This constraint guided effects on therapeutic translation, show promise in preclinical studies and tends to have low efficacy in clinical studies. Recent research focuses more on multifactorial models indicating the complexity of the syndrome. Multi-hit designs, CRISPR/Cas9 gene editing, humanized mice and nonrodent hosts are becoming more and more common. Also, more recent methods like multi-omics platforms, optogenetics, neuroendocrine imaging, gut microbiota transplants and AI-based simulations can enable mapping disease mechanisms sequentially, enabling more specific and targeted therapies. In harmony with these scientific breakthroughs, ethical and regulatory considerations are diminishing animal research and growing expenditure on organoids, ovary-on-chip platforms and stem cell based in vitro infrastructure. Such developments are harmonized with global commitments to the philosophy of 3Rs and with the news paradigm of an age of post-animal research. Future PCOS research will necessitate interdisciplinary perspective, explicit standard models, increased data sharing and model tailoring to particular phenotypes and populations.  The synergistic approach to these efforts has a potential to provide novel diagnostics, precision therapy and mechanistic insights that, in the future, are capable of redefining the knowledge and management of PCOS in diverse patient subsets.

    ACKNOWLEDGEMENT

    We express our gratitude to Ms. Pyari Payal Beura and Ms. Shibani Jena of SKR laboratory for their unwavering assistance and valuable recommendations regarding many elements of our assessment.
     
    Disclaimers
     
    NA.
     
    Funding
     
    Ms. Sulagna Dash Mohapatra was financially supported by Department of Biotechnology, Ministry of Science and Technology, Government of India with Fellowship number DBT/2025-26/RDWU/2717.

    CONFLICT OF INTEREST

    The authors declare no conflict of interest.

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