Ovarian fibrosis in polyendocrine metabolic ovarian syndrome: emerging mechanisms and therapeutic implications

Abstract

Polyendocrine metabolic ovarian syndrome (PMOS) remains a leading cause of anovulatory infertility worldwide, traditionally managed through systemic hormonal and metabolic stabilization. However, recent evidence has increasingly identified ovarian fibrosis, which is characterized by excessive extracellular matrix deposition and structural remodeling, as a critical hallmark of reproductive decline in affected individuals. This review provides a comprehensive synthesis of the evolving PMOS landscape, bridging the gap between classic endocrine dysfunction and the newly recognized fibrotic microenvironment. We systematically evaluate the pathogenesis of PMOS, ranging from hyperandrogenemia and insulin resistance to chronic low-grade inflammation, while detailing the molecular drivers of fibrosis such as the TGF-β/CTGF axis and mitochondrial exhaustion. Furthermore, we analyze current therapeutic modalities, including pharmacological agents, regenerative medicine, and traditional Chinese medicine, which highlight a paradigm shift toward precision interventions. Despite these advancements, the precise causal mechanisms linking PMOS to fibrotic pathology remain underexplored, and targeted curative strategies are scarce. We conclude by proposing that alleviating ovarian fibrosis through drug, metabolic, and immunomodulatory pathways represents a high-potential frontier. Future research should prioritize these anti-fibrotic strategies to not only alleviate symptoms but also fundamentally restore ovarian function and extend reproductive longevity.

Introduction

Polyendocrine metabolic ovarian syndrome (PMOS) is a complex and heterogeneous endocrine disorder that affects approximately 10–15% of women of reproductive age worldwide, serving as a primary driver of anovulatory infertility [1, 2]. Clinically, PMOS manifests as a constellation of symptoms including menstrual irregularities, hyperandrogenemia, chronic oligo- or anovulation, insulin resistance, obesity, and acne [3–5]. Beyond these reproductive and metabolic derangements, affected individuals exhibit an increased susceptibility to mood disorders, notably anxiety and depression [6]. Cumulatively, these health risks severely diminish quality of life and impose a substantial socioeconomic burden. However, because its multifactorial pathogenesis remains not yet fully elucidated, the development of targeted, curative therapies has been significantly hindered.

The traditional name for polycystic ovary syndrome (PCOS) has long been questioned because it focuses excessively on the morphological arrest of follicular development in the ovaries—rather than on true pathological cysts—and fails to encompass the disease’s broad range of systemic manifestations. In fact, the condition is far from a simple gynecological issue. It is a complex, multisystem network intertwined with endocrine, metabolic, reproductive, dermatological, and psychological disorders. To bridge the gap between the terminology and clinical reality, a new, more paradigm-shifting name—polyendocrine metabolic ovarian syndrome (PMOS)—has recently been formally proposed through a rigorous, multi-step global consensus process [7]. This update is not merely a semantic substitution. It shifts the scientific perspective from a localized description of the ovaries to a holistic understanding of the complex interactions among central neuroendocrine dysfunction, insulin resistance, compensatory hyperinsulinemia, and ovarian dysfunction. Consequently, it provides a more precise framework for elucidating the heterogeneous clinical manifestations and tissue-specific pathological mechanisms of this condition.

According to the EGOI-PCOS theory, the heterogeneous phenotypes of PCOS currently defined based on the Rotterdam criteria should be reclassified from a pathophysiological perspective [8]. Accordingly, the hyperandrogenic phenotypes previously classified as phenotypes A, B, and C should in fact be categorized under the umbrella of endocrine-metabolic syndrome (EMS), whose core features include hyperandrogenism, ovulatory dysfunction, and are often accompanied by insulin resistance or metabolic abnormalities [9]. In contrast, phenotype D, characterized by normal androgen levels, has been proposed as a distinct disease entity, termed Multifollicular Ovarian Disease (MFOD), whose pathophysiological mechanisms are primarily driven by ovarian factors and lack the typical background of hyperandrogenism and metabolic abnormalities [10].

Recent studies have indicated that PMOS is frequently associated with tissue fibrosis. Fibrosis, driven by inflammation and aberrant signaling, is defined by fibroblast proliferation and pathological extracellular matrix (ECM) deposition, ultimately leading to progressive organ dysfunction and failure [11–13]. Although extensively studied in major organs, ovarian fibrosis remains under-recognized despite its critical role in female fertility. Phenotypic differentiation is crucial for research on ovarian fibrosis, as the pathophysiological significance of fibrosis varies across different PMOS subtypes [14]. Fibrosis associated with the hyperandrogenic-metabolic subtype is closely linked to the endocrine-metabolic-inflammatory network, involving multiple mechanisms such as insulin resistance, hyperinsulinemia, excess androgens, oxidative stress, chronic inflammation, and extracellular matrix remodeling; in contrast, the androgen-normal MFOD-like phenotype may arise from different pathogenic pathways, and the two should not be equated [15]. The remainder of this article will focus on exploring the relationship between the hyperandrogenic-metabolic-abnormal phenotype and ovarian fibrosis.

However, despite growing recognition of the link between PMOS and fibrotic pathology, studies investigating whether targeting ovarian fibrosis could serve as an effective strategy to alleviate PMOS or restore ovarian function remain scarce, and the precise relationship between these two conditions remains largely unexplored. To address this gap, this narrative review aims to contextualize the mechanistic intersection between PMOS and ovarian fibrosis. By synthesizing current insights into PMOS pathogenesis alongside its associated fibrotic pathways, and by exploring the therapeutic potential of ameliorating ovarian fibrosis, this article seeks to propose novel directions for future translational research and clinical intervention.

Methods

To conduct a comprehensive analysis of disease heterogeneity and ovarian fibrosis, we performed a targeted literature search. Using keywords such as “polycystic ovary syndrome (PCOS),” “polyendocrine metabolic ovarian syndrome (PMOS),” “endocrine-metabolic syndrome (EMS),” “multimolecular ovary disease (MFOD),” and “ovarian fibrosis,” we searched the PubMed and Google Scholar databases for literature published up to 2026. We focused primarily on peer-reviewed research articles and high-impact-factor review articles, which provided in-depth insights for the writing of this paper.

The evaluation criteria and pathogenesis of PMOS

The evaluation criteria of PMOS

The diagnostic landscape of PMOS has undergone a century-long transformation, evolving from a focus on gross ovarian morphology to a sophisticated understanding of endocrine dysfunction and clinical heterogeneity [16]. This journey began in 1844 with the initial morphological descriptions by Chereau and Rokitansky [17, 18], eventually reaching a clinical milestone in 1935 when Stein and Leventhal defined the classic triad of amenorrhea, hirsutism, and polycystic ovaries [19]. During the late 20th century, the advent of biochemical assays and ultrasonography sparked a “diagnostic tug-of-war” between various international bodies. The 1990 NIH criteria initially adopted a stringent approach, requiring both hyperandrogenism and ovulatory dysfunction for diagnosis [20].

However, the 2003 Rotterdam consensus revolutionized the field by introducing the ‘two-out-of-three’ rule—incorporating polycystic ovary morphology (PCOM) as a key pillar alongside hormonal and ovulatory markers [21, 22]. Although the 2006 AES criteria briefly attempted to center the diagnosis solely on hyperandrogenism, the Rotterdam framework ultimately prevailed due to its ability to encompass the syndrome’s diverse manifestations [23, 24].Currently, the scientific community recognizes PMOS as a spectrum of four distinct clinical phenotypes (Types A–D), ranging from the “classic” high-risk metabolic states to milder non-androgenic variants [25].

The latest 2018 and 2023 international evidence-based guidelines have further refined this framework with surgical precision. These updates emphasize the critical need to exclude “mimics” like Cushing’s syndrome, establish more cautious diagnostic thresholds for adolescents (prioritizing biochemical markers over ultrasound), and upgrade PCOM criteria to 20 follicles to account for the increased sensitivity of modern high-frequency imaging [26, 27]. This progression reflects a shift toward precision medicine, acknowledging that PMOS is not a monolithic condition but a complex interplay of metabolic and reproductive disturbances (Fig. 1).

Fig. 1.

Evolution and current framework of PMOS diagnostic criteria. The timeline illustrates the paradigm shift from gross morphological descriptions (1844–2026) to a sophisticated functional framework. Key milestones include the 1990 NIH criteria, the “gold standard” 2003 Rotterdam consensus defining four clinical phenotypes (Types A–D), and the 2006 AES androgen-centric approach. Modern 2018–2026 guidelines emphasize precision medicine through the exclusion of secondary mimices, specific diagnostic requirements for adolescents, and an upgraded PCOM threshold (≥ 20 follicles) to account for high-frequency imaging advances. This progression reflects the transition toward recognizing PMOS as a heterogeneous spectrum of reproductive and metabolic disturbances

The pathogenesis of PMOS

Hyperandrogenemia is a central diagnostic phenotype and a key driver of PMOS pathology [28]. In women, androgens are primarily synthesized by the adrenal cortex and ovaries, with precursors such as DHEA, DHEA-S, and androstenedione undergoing peripheral conversion [29]. In PMOS, excess androgens—largely of ovarian origin—arrest follicular development at the antral and preantral stages, preventing progression to Graafian follicles and ovulation, ultimately resulting in anovulatory infertility [30, 31]. This hyperandrogenic state is perpetuated by dysregulated hypothalamic-pituitary-ovarian axis function, particularly increased GnRH pulse frequency that resists negative feedback regulation, thereby sustaining excessive ovarian androgen production [32–34].

Insulin resistance is a prevalent metabolic disturbance in PMOS that contributes significantly to both metabolic dysfunction and reproductive pathology [35, 36]. Mechanistically, it involves impaired signaling through the PI3-K, MAPK, and ERK pathways, which disrupts glucose uptake [35, 37]. The resulting hyperinsulinemia reduces hepatic synthesis of sex hormone-binding globulin (SHBG), elevating free androgen levels, while also directly stimulating ovarian theca cell androgen production [36, 38, 39]. These effects synergize with LH to further exacerbate hyperandrogenemia. Specifically, the chronic synergistic overstimulation by hyperinsulinemia and elevated LH induces ovarian hyperthecosis, characterized by pathological hypertrophy and hyperplasia of theca interna cells. This structural expansion fundamentally amplifies the steroidogenic capacity of the ovaries, creating a vicious cycle of androgen excess. Notably, hyperandrogenism can also occur in PMOS patients without overt insulin resistance, indicating that multiple pathways contribute to the hormonal phenotype.

Follicle development is regulated by several factors, notably FSH and LH. These hormones are modulated by estradiol and progesterone, secreted by the ovaries, which regulate follicle maturation and ovulation [40–42]. The hypothalamic-pituitary-gonadal axis is crucial in regulating this process [43]. In PMOS patients, an elevated LH/FSH ratio, driven by rapid GnRH pulsatility, coupled with relative FSH deficiency, arrests follicular development [44].

Chronic low-grade inflammation is increasingly recognized as a key component of PMOS pathophysiology [45]. Patients exhibit elevated levels of inflammatory mediators, including CRP, TNF-α, interleukins (IL-6, IL-8, IL-18), MCP-1, and increased white blood cell counts [46–48]. These inflammatory factors adversely affect ovarian function, metabolism, and androgen levels. Additionally, PMOS is associated with endometrial immune dysregulation, where a heightened inflammatory state may compromise implantation and increase miscarriage risk [49, 50]. Advanced glycation end products (AGEs), which are elevated in PMOS, further contribute to oxidative stress and impair the function of ovarian theca and granulosa cells [51, 52]. Collectively, these inflammatory mechanisms reinforce the endocrine and reproductive disturbances characteristic of the syndrome.

In addition to the factors mentioned above, abnormalities in mitochondrial morphology and function in PMOS patients can affect energy metabolism and glucose uptake, mediated by the mTOR signaling pathway in B cells [53]. Additionally, studies indicate that epigenetic alterations, such as DNA methylation, influence androgen changes in PMOS patients [54]. The etiology of PMOS still requires further exploration (Fig. 2).

Fig. 2.

Pathophysiological landscape and multifactorial etiology of PMOS. The schematic illustrates the synergistic interplay between neuroendocrine, metabolic, and cellular drivers of the syndrome. Neuroendocrine dysregulation is characterized by rapid GnRH pulsatility and elevated LH/FSH ratios, stimulating ovarian androgen synthesis. Metabolic dysfunction involves impaired PI3-K/MAPK/ERK signaling and hyperinsulinemia, which suppresses hepatic SHBG to elevate free androgens. Chronic inflammation and oxidative stress, driven by pro-inflammatory cytokines (TNF-α, ILs) and AGEs, disrupt the follicular microenvironment. Furthermore, cellular and epigenetic mechanisms, including mTOR-mediated mitochondrial dysfunction and DNA methylation of androgen-related genes, contribute to follicular arrest, hyperthecosis, and endometrial immune dysregulation. Collectively, these pathways underscore the syndrome’s complex reproductive and metabolic manifestations

The pathogenic landscape of ovarian fibrosis

Ovarian fibrosis is a pathological hallmark characterized by the excessive and aberrant accumulation of ECM components within the ovarian stroma. This progressive deposition triggers profound structural remodeling, which serves as a precursor to the decline of ovarian physiological function [55]. Emerging clinical and experimental evidence underscores a significant association between PMOS and the manifestation of ovarian fibrotic changes [56]. The pathogenesis of this condition is orchestrated by a sophisticated and dynamic interplay between pro-fibrotic signaling cascades and endogenous homeostatic inhibitors. When this regulatory balance is disrupted, the resulting fibrotic microenvironment compromises follicular maturation and significantly curtails the overall reproductive lifespan.

The central role of TGF-β and CTGF in fibrogenesis

Transforming growth factor beta (TGF-β), through its three isoforms, serves as a master regulator of ovarian physiology, including follicular recruitment and FSH sensitivity [57, 58]. However, abnormally elevated TGF-β1 triggers pathological Smad-dependent and non-Smad pathways, leading to follicular dysplasia and ovulation failure [59]. It drives the epithelial-mesenchymal transition (EMT) and ECM deposition, a process further amplified by Connective Tissue Growth Factor (CTGF) [60–62]. CTGF, acting as a downstream effector of TGF-β and Hippo pathways, promotes fibrogenesis via autocrine and paracrine signaling in granulosa cells and fibroblasts [63, 64]. Consequently, the synergistic interplay between TGF-β and CTGF signaling forms a core pathogenic axis that accelerates the progression of ovarian fibrosis and undermines the functional longevity of the ovary.

Extracellular matrix remodeling and pathological deposition

The ECM is a dynamic macromolecular network essential for follicular maturation, yet its progressive accumulation is a hallmark of ovarian aging and fibrosis [65–67]. The balance of the ECM is maintained by matrix metalloproteinases (MMPs), which are regulated by signaling kinases such as MAPK, Akt, and ERK1 [68–70]. Excessive ECM deposition, stimulated by factors like platelet endothelial aggregation receptor 1 and various proteases (ADAM, ADAMTS), creates a rigid microenvironment that exacerbates the progression of aberrant fibrosis [71, 72]. This transition results in a rigid stromal microenvironment that acts as a mechanical barrier to healthy follicular dynamics.

Crucially, it is necessary to address a common clinical paradox: while ovarian fibrosis is traditionally associated with follicular depletion and a poor ovarian response (as seen in ovarian aging), PMOS-associated fibrosis presents a distinct pathological paradigm. In PMOS, the rigid fibrotic stroma acts as a mechanical barrier that restricts follicular expansion, leading to severe follicular arrest rather than apoptotic depletion. Consequently, a massive cohort of small antral follicles accumulates and survives within this rigid microenvironment, continuously secreting high levels of Anti-Müllerian Hormone (AMH). This fibrotic-induced ‘follicular trapping’ perfectly reconciles the presence of severe stromal fibrosis with the classic PMOS clinical hallmarks of a high antral follicle count (AFC), elevated AMH levels, and a high ovarian response to exogenous stimulation.

Inflammation as a catalyst for ovarian fibrosis

Chronic inflammation and tissue injury are pivotal triggers for fibrogenesis. In the ovary, the recruitment of T cells and macrophages fosters a pro-fibrotic environment by modulating reactive oxygen species and cytokines through TGF-β and PDGF pathways [73, 74]. During ovarian aging, fibroblasts further exacerbate this process by promoting inflammatory responses [75]. Persistent elevation of inflammatory markers, specifically IL-6 and IL-8, induces fiber formation around the ovaries, which can ultimately culminate in ovulatory failure [76].

Endogenous inhibitors: BMP-7, PPAR-γ, and VEGF

Conversely, several molecular pathways act as inhibitors to counteract ovarian fibrosis. Bone morphogenetic protein 7 (BMP-7) antagonizes the pro-fibrotic TGF-β/Smad axis, thereby alleviating EMT and promoting normal follicular development [77–79]. Peroxisome proliferator-activated receptor gamma (PPAR-γ) also plays a protective role; its agonists, such as rosiglitazone, reduce TGF-β expression in granulosa cells [80]. Furthermore, Vascular Endothelial Growth Factor (VEGF) supports fertility by regulating angiogenesis and has been shown to ameliorate fibrosis in various tissues, suggesting its potential to inhibit the vicious cycle of ECM overproduction in the ovary [81–84]. Harnessing these inhibitory mechanisms may therefore offer novel therapeutic avenues to preserve ovarian function and extend the reproductive lifespan in the face of fibrotic challenges (Fig. 3).

Fig. 3.

The pathogenic landscape of ovarian fibrosis. Pathological fibrogenesis in the ovary, associated with PMOS and aging, leads to follicular dysplasia and ovulation failure by transforming a soft ECM into a rigid microenvironment. The pro-fibrotic signaling axis (bottom left) centers on abnormally elevated TGF-β1, which drives both Smad-dependent and non-Smad pathways, inducing epithelial-mesenchymal transition (EMT). CTGF, an effector amplified by TGF-β and Hippo pathways, further accelerates fibrogenesis and excessive ECM deposition, which is also stimulated by platelet-derived PDGF and proteases (ADAM, ADAMTS) that disrupt ECM remodeling by MMPs. Chronic inflammation involves T cell and macrophage recruitment, fostering pro-fibrotic conditions through reactive oxygen species and inflammatory cytokines (IL-6, IL-8, PDGF). Conversely, endogenous inhibitors offer therapeutic avenues (bottom right) to restore the regulatory balance (top right): BMP-7 antagonizes the TGF-β/Smad pathway to inhibit EMT; PPAR-γ agonists (rosiglitazone) reduce TGF-β expression in granulosa cells; and VEGF promotes angiogenesis to inhibit ECM overproduction, thereby protecting follicular dynamics

Clinical trials of potential treatments for PMOS

Drugs that regulate insulin resistance, hormones and ovulation

Metformin and letrozole remain a cornerstone in the pharmacological management of PMOS, where it not only improves ovulation—demonstrating superior efficacy as a monotherapy compared to agents like clomiphene citrate—but also enhances peripheral insulin sensitivity and reduces total testosterone levels [85–87]. Its mechanism is largely attributed to modulation of mitochondrial function and metabolic pathways, including the tricarboxylic acid cycle. Inositol, including its myo-inositol (MI) and D-chiro-inositol (DCI) isomers, offers insulin-like effects that improve insulin sensitivity, reduce hyperandrogenemia, and restore menstrual cyclicity, partly by stimulating insulin secretion from pancreatic beta cells [88]. In select cases, oral corticosteroids such as dexamethasone are used to directly suppress androgen production [89, 90]. Moreover, for patients with significant insulin resistance, combination strategies—such as metformin with thiazolidinediones—may yield additive benefits [91]. Together, these therapeutic approaches target the core metabolic and endocrine disruptions underlying PMOS.

Lifestyle improvements and surgical treatment

Beyond pharmacotherapy, lifestyle modification plays a key adjunctive role in PMOS management. The Mediterranean diet, rich in antioxidants, unsaturated fats, and fiber, offers anti-inflammatory benefits that support weight control and metabolic health [92, 93]. Combined with regular physical activity, smoking cessation, and healthy sleep habits, such interventions improve insulin sensitivity, hormonal balance, and overall clinical outcomes [94].

Surgical treatment is an alternative for individuals unresponsive to drug therapies, such as those with insulin sensitivity drug resistance or those not achieving significant therapeutic effects from medication. Common surgical approaches include laparoscopic ovarian drilling [95], follicular aspiration via transvaginal ultrasonography, and assisted reproductive technology.

Stem cell and exosomes therapy

Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic strategy for PMOS by targeting its underlying metabolic and endocrine disturbances [96]. In preclinical models, MSCs restore ovarian function and improve metabolic dysfunction through interleukin-10 secretion [97]. Bone marrow-derived MSCs reduce androgen levels via BMP-2-mediated regulation of steroidogenic genes [98]. Additionally, MSC-derived exosomes exert angiogenic, anti-inflammatory, and anti-apoptotic effects, with microRNAs playing key roles in ameliorating metabolic abnormalities. Stem cell-derived apoptotic vesicles ameliorate ovarian dysfunction in Polyendocrine metabolic ovarian syndrome and ovarian aging via WNT signaling–mediated regulation of folliculogenesis, highlighting the potential of stem cell secretomes in reproductive repair [99]. Despite these encouraging findings, MSC-based therapies for PMOS remain at the preclinical or early clinical stage, warranting further investigation into their safety and efficacy.

Traditional Chinese medicine therapy

In China, traditional Chinese medicine (TCM) offers effective therapeutic options for PMOS through bioactive small molecules targeting key pathogenic pathways. Guizhi Fuling Wan improves insulin resistance and follicle development via PI3K/Akt signaling and Cyp19a1 upregulation [100]. Cangfudaotan decoction enhances insulin sensitivity through the IGF-1-PI3K/Akt-Bax/Bcl-2 axis. Bao Gui capsule reduces hyperandrogenemia and insulin resistance by modulating P450c17α, P450arom, and GLUT4 expression [101–103]. Dingkun pills, often combined with Diane-35, lower androgen levels and improve menstrual cyclicity [104, 105]. Collectively, these TCM-derived compounds exert multi-target effects on metabolic and endocrine dysfunction in PMOS (Fig. 4).

Fig. 4.

Clinical trials of potential treatments for PMOS. The schematic categorizes current and prospective management strategies into four functional domains aimed at restoring ovarian function and fertility (1). Pharmacological regulation focuses on metabolic and hormonal control via metformin, inositols, and dexamethasone, targeting the TCA cycle and insulin sensitivity (2). Lifestyle and surgical interventions provide systemic support through anti-inflammatory diets and exercise, alongside structural approaches like laparoscopic ovarian drilling (LOD) (3). Advanced cell and exosome therapy utilizes MSC-derived secretomes and microRNAs to promote folliculogenesis and anti-apoptosis via Wnt and BMP-2 signaling (4). Traditional Chinese Medicine (TCM) exerts multi-target effects on the PI3K/Akt axis and GLUT4 expression. Collectively, these multifaceted approaches address the complex endocrine-metabolic heterogeneity of the syndrome

Pathogenesis and therapeutic advances in ovarian fibrosis during PMOS progression

Core pathogenic mechanisms of ovarian fibrosis in PMOS

Recent advances in elucidating the core mechanisms of ovarian fibrosis in PMOS suggest that this pathological process is primarily driven by hyperandrogenism through an orchestrated cascade of interconnected pathways [56, 106]. At the center of this axis, excessive androgens activate the p300-SP1-BRD4 transcriptional complex, which utilizes histone acetylation to enhance the transactivation of the androgen receptor (AR), directly upregulating pro-fibrotic gene expression [56]. Concurrently, the activation of the NLRP3 inflammasome in granulosa cells triggers pyroptosis, releasing pro-inflammatory cytokines that facilitate mesenchymal transition within the stroma [106]. Simultaneously, endoplasmic reticulum (ER) stress via the IRE1α pathway and oxidative stress via ROS accumulation act synergistically to activate the canonical TGFβ1/Smad signaling cascade, reinforcing the fibrotic progression [107]. Emerging evidence also highlights the roles of ferroptosis (the METTL3/GPX4 axis) and mitochondrial metabolic exhaustion in driving excessive ECM deposition [108]. Together, these intersecting pathways form a robust and complex pro-fibrotic network.

Potential therapeutic targets for mitigating ovarian fibrosis in PMOS

The therapeutic paradigm for PMOS is increasingly shifting from systemic hormonal stabilization toward precision intervention within the fibrotic ovarian microenvironment. At the epigenetic level, targeting BRD4 (using inhibitors like JQ1) or p300 offers the potential to arrest the androgen-driven transcriptional program at its source [109]. Metabolic interventions centered on NAD+ precursors and the exercise-induced myokine Irisin aim to rejuvenate mitochondrial function and alleviate ER stress to restore metabolic homeostasis [107]. Immunomodulatory targets, such as NLRP3 inhibitors Vitexin and IL-18BP, focus on disrupting the transition from chronic inflammation to permanent fibrosis [106]. Furthermore, proanthocyanidins have garnered significant interest due to their low toxicity and ability to antagonize TGF-β signaling [110].

Emerging evidence underscores the significant potential of inositol as a multi-target modulator in regulating tissue fibrosis. In classic pulmonary fibrosis models, inositol exerts broad molecular targeting effects; it not only markedly downregulates pro-fibrotic signaling pathways centered on EGFR, PKC, AKT, and STAT3, but also suppresses the activation of their downstream effector, MARCKS. This multi-kinase inhibition ultimately thwarts the phenotypic conversion of fibroblasts into highly invasive myofibroblasts. Consequently, this molecular blockade translates into a striking reduction in the expression of crucial fibrotic markers, including COL1A1 and α-SMA, thereby attenuating bleomycin-induced fibrotic lesions and collagen deposition in vivo [111].

Intriguingly, in secondary fibrosis models associated with acute respiratory distress syndrome (ARDS), inositol has been shown to restore autophagy flux and impede EMT via the precise orchestration of the HIF-1α/SLUG axis [112]. Although these findings are derived from non-ovarian tissues, the shared pathways brought to light—such as ECM remodeling, myofibroblast inactivation, the blockade of EMT/MMT, and the mitigation of localized inflammation and oxidative stress—are biologically congruent with the core pathogenesis of ovarian fibrosis. This cross-organ mechanistic conservation provides a compelling rationale for exploring inositol as a novel therapeutic candidate to ameliorate ovarian fibrosis and microenvironmental deterioration driven by advanced age or pathological insults.

Finally, regenerative strategies, such as the use of menstrual blood-derived mesenchymal stem cells and their secretomes, provide a promising path for structural remodeling and the reversal of stromal stiffness, ultimately aiming to preserve and extend reproductive longevity [113]. The therapeutic paradigm for PMOS is shifting from systemic hormonal regulation toward precision intervention within the ovarian microenvironment, with a central focus on combating fibrosis, (Fig. 5).

Fig. 5.

Potential therapeutic targets for mitigating ovarian fibrosis in PMOS. The schematic delineates the pro-fibrotic network driven by hyperandrogenism and the corresponding targeted interventions. (Left) Pathogenic mechanisms center on androgen-mediated p300-SP1-BRD4 complex activation, NLRP3-driven pyroptosis, and IRE1α-mediated ER stress, which collectively trigger the canonical TGF-β1/Smad axis and pathological ECM deposition. Additional factors like mitochondrial metabolic exhaustion and ferroptosis (METTL3/GPX4 axis) further exacerbate stromal rigidity. (Right) Precision strategies target these specific nodes: epigenetic blockers (JQ1) arrest pro-fibrotic transcriptional programs; NAD⁺ precursors and Irisin restore metabolic homeostasis; immunomodulators (Vitexin, IL-18BP) inhibit inflammatory cascades; and natural compounds (Resveratrol) neutralize TGF-β1. Finally, regenerative medicine using MenSCs offers structural remodeling, marking a paradigm shift toward microenvironment-targeted precision therapy. Inositol reduces the expression of COL1A1 and α-SMA by inhibiting multiple pro-fibrotic signaling pathways such as EGFR, PKC, AKT, and STAT3, as well as the activation of downstream MARCKS. On the other hand, it blocks epithelial-mesenchymal transition (EMT) and the phenotypic transformation of fibroblasts into myofibroblasts by regulating the HIF-1α/SLUG axis

Discussion

PMOS is a multifaceted endocrine disorder, with its pathogenesis influenced by diverse factors. Recent advancements in research on the pathogenesis of PMOS have significantly contributed to the development of its therapeutic methods.

Recent studies have revealed significant differences in the intestinal flora of PMOS patients compared to the control group [114]. The dysbiosis of the intestinal microbiome in female PMOS patients is linked to neuroendocrine alterations and affects serum LH levels [115] and glucose metabolism [116]. Research has shown a significant elevation of Bacteroides vulgatus in the intestinal flora of PMOS patients. Furthermore, transplanting Bacteroides into normal mice has been observed to induce certain PMOS characteristics. This study suggests that the gut microbiota-bile acid-interleukin-22 axis plays a synergistic role in regulating PMOS, offering new insights for its treatment [117].

PMOS frequently exhibits features of insulin resistance, leading to metabolic abnormalities and associated conditions like hypertension, diabetes, dyslipidemia, and glucose intolerance. Patients with PMOS face a significant risk of developing cardiovascular diseases. However, lifestyle interventions and weight management can mitigate the risk of these potential cardiovascular diseases [118]. Recent studies also indicate an elevated risk of depression in PMOS patients, potentially due to obesity, hirsutism, acne, and androgenic alopecia associated with the condition [119]. Greater emphasis should be placed on maintaining the mental health of patients when treating PMOS.

As an endocrine disorder, PMOS is characterized by reproductive and metabolic disturbances. Currently, PMOS treatment primarily involves pharmacotherapy, including drugs that regulate insulin sensitivity and hormonal medications. Long-term use of these drugs for PMOS treatment may result in adverse effects on the body. Recently, various Chinese medicinal treatments have gained popularity as novel approaches to managing PMOS [120, 121]. In comparison to Western medicine, Chinese medicine offers several benefits in the management of PMOS [122]. This clinical evidence highlighting the beneficial effects of traditional Chinese medicine in PMOS management deepens our understanding of PMOS pathophysiology and contributes new insights into the mechanisms through which traditional Chinese medicine affects PMOS treatment.

The identification of ovarian fibrosis as a core pathological hallmark of PMOS marks a significant paradigm shift in our understanding of anovulatory infertility. Beyond traditional endocrine imbalances, the aberrant accumulation of ECM within the ovarian stroma creates a restrictive mechanical environment that fundamentally impairs follicular maturation and ovulation. It is important to emphasize that PMOS-associated fibrosis does not equate to ovarian exhaustion; instead, the fibrotic stroma locks the excessively recruited follicles in an arrested state. This unique mechanical restriction clarifies why patients concurrently exhibit stromal fibrosis and hyper-responsiveness markers, such as high AFC and elevated AMH.

Evidence across clinical and experimental models consistently points to hyperandrogenism as the primary upstream driver, orchestrating a pro-fibrotic network through the p300-SP1-BRD4 transcriptional axis and the canonical TGFβ1/Smad pathway [123]. Furthermore, the convergence of multiple cellular stressors, ranging from NLRP3-mediated pyroptosis and endoplasmic reticulum stress to ferroptosis, underscores the multifaceted nature of stromal decay [124]. While animal models have been instrumental in dissecting these molecular cascades, translating these findings into precision therapies remains a critical challenge. Emerging strategies targeting epigenetic readers, such as BRD4 inhibitors, or metabolic rejuvenators like NAD⁺ precursors, offer promising avenues to arrest fibrotic progression [107, 109]. Ultimately, restoring the biophysical and biochemical homeostasis of the ovarian niche is essential for enhancing reproductive longevity and improving clinical outcomes for women with PMOS.

Furthermore, research on the direct mechanisms underlying ovarian fibrosis in human PMOS patients remains very limited at present. Although macroscopic structural abnormalities, such as the proliferation of the theca and thickening of the ovarian cortex, have been well documented in clinical specimens from patients, due to the severe limitations on the ethical and clinical acquisition of human ovarian biopsy samples, understanding of the underlying molecular mechanisms of progressive stromal fibrosis and dynamic ECM remodeling currently relies primarily on rodent models and in vitro cell culture. Due to physiological differences between species, these findings derived from animal models and cellular experiments still have certain limitations in explaining the specific pathological mechanisms underlying different disease phenotypes in humans.

Moreover, although we have identified several potential fibrosis pathways in animal studies, clinical data remain scarce regarding whether interventions targeting these pathways can effectively alleviate the heterogeneous phenotypes observed in human patients or restore their ovarian function and fertility; further preclinical and clinical investigations are therefore needed.

Clinical perspective

Clinically, polyendocrine metabolic ovarian syndrome (PMOS) is commonly associated with impaired reproductive function in women of childbearing age. Accumulating evidence suggests that ovarian fibrosis and the resulting stromal remodeling represent a potential pathological mechanism underlying abnormal follicle development. Guided by the EGOI-PCOS theory, this review discusses the heterogeneity of fibrosis between the EMS and MFOD phenotypes. Based on these insights, we suggest that clinical management could expand from systemic hormonal regulation to include the assessment of the localized ovarian microenvironment. We also systematically summarize potential therapeutic strategies to ameliorate ovarian fibrosis. However, direct data from human clinical specimens remain limited. Therefore, rigorous translational studies are urgently needed to objectively evaluate the clinical efficacy and safety of targeted interventions—such as pharmacological agents, metabolic modulators, and regenerative medicine—in alleviating ovarian fibrosis and optimizing assisted reproductive technology (ART) outcomes.

Conclusions

In conclusion, ovarian fibrosis is a pivotal yet poorly understood driver of reproductive decline in PMOS. Addressing the current deficit in our understanding of its pathogenic mechanisms and the lack of targeted anti-fibrotic therapies is essential. This review underscores the necessity of mapping the molecular pathways governing PMOS-associated fibrosis to uncover novel therapeutic targets. Ultimately, elevating clinical awareness and developing mechanism-driven interventions to mitigate fibrosis offer a compelling strategy to reverse ovarian dysfunction and optimize assisted reproductive technology outcomes for patients with PMOS.

Authors’ contributions

Mengqing Gu, Jing Wang and Yang Yu establish review idea, information collection and writing. Zhonghong Zeng conducted the literature search and data collection.

Funding

This work was supported by the National Key R&D Program of China (2024YFC2706600), the National Natural Science Foundation of China (82225019, 82192873) and the Beijing Nova Program (20240484604), the Tianfu Jincheng Laboratory Foundation (TFJCPI20250032).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.