Natural Products for Polyendocrine Metabolic Ovarian Syndrome: Integrating Traditional Chinese and Western Medicine Perspectives

Abstract

Polyendocrine metabolic ovarian syndrome (PMOS), the new consensus nomenclature renamed from polycystic ovary syndrome (PCOS) in 2026 by The Lancet global expert consortium, is a prevalent multisystem endocrine-metabolic disorder affecting reproductive-age women worldwide. The traditional term PCOS is scientifically inaccurate as it misleadingly emphasizes pathological ovarian cysts while ignoring the complex polyendocrine, metabolic, and systemic pathological characteristics of the disease, which also leads to delayed diagnosis and fragmented clinical management. PMOS is characterized by the core pathological vicious cycles of insulin resistance, hyperandrogenism, chronic low-grade inflammation, and oxidative stress, substantially elevating the risk of type 2 diabetes, cardiovascular diseases, and endometrial carcinoma. Mitochondrial dysfunction and gut microbiota dysbiosis play key roles as emerging pathological factors in PMOS. Traditional Chinese medicine (TCM) interprets PMOS pathogenesis as dysfunction of the kidney-tiangui-chong-ren-baogong axis, with spleen deficiency, liver qi stagnation, phlegm-dampness and blood stasis as key syndrome patterns. Natural products, as the core material basis of TCM, possess multi-component and multi-target pharmacological properties, which perfectly fit the complex multisystem pathophysiological attributes of PMOS emphasized in the latest global consensus. This comprehensive review systematically elaborates the dual-pathogenesis of PMOS from Western medicine and TCM perspectives in line with the 2026 Lancet consensus. We further clarify the mechanism by which natural products exert therapeutic effects on PMOS via improving glucose metabolism, regulating lipid homeostasis, and ameliorating hyperandrogenism. This work aims to provide a standardized theoretical reference for basic precision research and clinical translational application of natural products in the management of PMOS.

Introduction

Polyendocrine metabolic ovarian syndrome (PMOS), newly renamed from polycystic ovary syndrome (PCOS) in the 2026 global consensus released in The Lancet, is one of the most common multisystem endocrine-metabolic disorders in reproductive-age women globally.1 The conventional term PCOS is scientifically inaccurate, as it overstates pathological ovarian cysts and neglects the disease’s intrinsic polyendocrine disturbance, metabolic dysfunction, and systemic manifestations, further resulting in delayed diagnosis and fragmented clinical care.2 Pathologically, PMOS is driven by the vicious interplay of insulin resistance (IR), hyperandrogenism (HA), chronic low-grade inflammation and oxidative stress (OS), which markedly increase the long-term risks of type 2 diabetes, cardiovascular diseases and endometrial carcinoma.3 Mitochondrial dysfunction and gut microbiota dysbiosis play key roles as emerging pathological factors in PMOS. From the perspective of traditional Chinese medicine (TCM), PMOS originates from the dysfunction of the kidney–tiangui–chong-ren–baogong axis, a theoretical framework of female reproductive regulation broadly corresponding to the hypothalamic–pituitary–ovarian (HPO) axis. Its major syndrome patterns include kidney deficiency, spleen deficiency, liver qi stagnation, phlegm-dampness (associated with metabolic dysfunction), and blood stasis (associated with impaired circulation). Natural products, as the essential material basis of TCM, exhibit multi-component and multi-target pharmacological features that well match the complex multisystem pathophysiology of PMOS highlighted by the latest consensus.

The etiology of PMOS is multifactorial and remains incompletely elucidated, involving a complex interplay of genetic predispositions, environmental factors, and intricate endocrine-metabolic dysregulations.4,5 At its core, PMOS is characterized by a synergistic pathological network encompassing IR, HA, chronic low-grade inflammation, and OS.6–8 These interconnected pathways form a vicious cycle of metabolic abnormality-hormonal disorder-inflammation/OS, driving disease progression and exacerbating associated complications. Specifically, IR acts as a pivotal nexus, promoting androgen synthesis and inducing dyslipidemia,9,10 while HA, in turn, aggravates IR. Concurrently, inflammation and OS amplify these pathological effects by impairing metabolic organ function and disrupting the ovarian microenvironment.11,12

Currently, the treatment of PMOS primarily involves individualized medication and lifestyle interventions, tailored to the patient’s specific symptoms.13 Lifestyle interventions are a cornerstone in managing PMOS, particularly in individuals with excess weight.14 Oral contraceptives are a commonly used treatment, but they may have adverse effects on glucose tolerance and fertility.15,16 Studies have shown that long-term use of oral contraceptives may be closely associated with conditions such as hypertension, venous thrombosis, and breast cancer.17,18 Consequently, it is particularly important to develop new therapeutic drugs that are safe, highly selective, and associated with fewer adverse reactions. In recent years, natural products have garnered significant attention in the field of PMOS treatment because they demonstrate therapeutic potential that surpasses that of traditional single-target drugs, offering the advantages of multi-target and multi-stage treatment.19 Furthermore, they have fewer side effects and reduce patients’ dependence on medication, providing an effective alternative treatment option for women with PMOS.3 A growing body of research has demonstrated that natural products can treat PMOS by regulating and improving glucose and lipid metabolism, and balancing sex hormone levels, thereby offering new candidate molecules and therapeutic strategies.

Although there is a wealth of research on PMOS, there is a lack of comprehensive, systematic reviews on the pharmacological mechanisms by which natural products treat PMOS through the regulation of glucose and lipid metabolism and HA. This review systematically interprets the pathogenesis of PMOS from both Western medicine and TCM perspectives, and further summarizes the mechanisms by which natural products treat PMOS through improving glucose metabolism, regulating lipid metabolism, and modulating HA, aiming to provide a theoretical basis for precise basic research and clinical translation of natural products in PMOS intervention.

Western Medical Perspectives on PMOS Pathogenesis

PMOS, from a western medical standpoint, is characterized by a complex interplay of multiple factors and pathways, where various pathological processes are interconnected and mutually causative. This intricate network collectively contributes to the clinical manifestations of ovulatory dysfunction, HA, and metabolic abnormalities (Figure 1).

Figure 1.

The pathogenesis of PMOS from western medical perspective. Reactive oxygen species (ROS); interleukin-6 (IL-6); tumor necrosis factor-α (TNF-α); luteinizing hormone (LH); follicle-stimulating hormone (FSH); short-chain fatty acids (SCFAs); lipopolysaccharide (LPS); mitochondrial DNA (mtDNA).

The Vicious Cycle of IR and HA

IR and HA represent the most central pathological components of PMOS, forming a self-perpetuating vicious cycle that is a key driver of disease progression.20

IR as a Central Metabolic Hub

IR refers to a diminished sensitivity of target tissues to insulin, prompting pancreatic β-cells to hypersecrete insulin in a compensatory effort to maintain glucose homeostasis, leading to hyperinsulinemia (HI). HI exerts its pathological effects in PMOS through several key mechanisms. It synergizes with luteinizing hormone (LH) to act on ovarian theca cells, activating steroidogenic enzymes such as cytochrome P450 family 17 subfamily A member 1 (CYP17A1), thereby promoting the synthesis and release of androgens.9 Additionally, HI directly stimulates ovarian granulosa cells to express LH receptors, insulin receptors, and insulin-like growth factor receptors, augmenting LH’s biological activity and further promoting androgen secretion.21 Furthermore, HI suppresses hepatic synthesis of sex hormone-binding globulin (SHBG), leading to an increase in serum free androgen levels and exacerbating HA. It also enhances the adrenal gland’s responsiveness to adrenocorticotropic hormone stimulation, thereby promoting the secretion of adrenal-derived androgens.22–24

HA from Ovarian and Adrenal Contributions

HA is a hallmark clinical manifestation of PMOS, primarily evidenced by elevated serum testosterone levels, and clinically presenting as acne, hirsutism, and female pattern hair loss.25 In PMOS patients, ovarian androgen overproduction is the predominant source of HA.25 During follicular development, theca cells, under LH stimulation, synthesize androgens. Granulosa cells, in contrast, express follicle-stimulating hormone (FSH) receptors and activate aromatase to convert these androgens into estradiol and estrone.

In PMOS patients, dysregulation of the HPO axis leads to an increased frequency of gonadotropin-releasing hormone release from the hypothalamus, resulting in excessive LH secretion and relatively insufficient FSH secretion, elevating the LH/FSH ratio.26 High LH levels continuously stimulate theca cells to secrete androgens, while low FSH levels hinder the effective activation of granulosa cell aromatase activity, impeding androgen-to-estrogen conversion. This creates an intra-ovarian hyperandrogenic microenvironment that inhibits follicular maturation and dominant follicle formation, ultimately leading to ovulatory dysfunction. Concurrently, peripheral conversion of androstenedione to estrone by cytochrome P450 family 19 subfamily a member 1 (CYP19A1) contributes to a state of hyperestronemia. The synergistic action of estrone and estradiol creates an abnormal positive feedback loop on the HPO axis, sustaining high LH levels without cyclicity, thus perpetuating the HA-anovulation vicious cycle and ultimately leading to polycystic ovarian morphology.26 The relationship between IR and HA is bidirectional and mutually reinforcing, as HA can further impair insulin signaling pathways, thereby exacerbating IR, forming a detrimental IR-HA vicious cycle.

Chronic Inflammation and OS

Chronic low-grade inflammation and OS are critical drivers in the pathogenesis of PMOS, forming a vicious cycle that further exacerbates IR and ovarian dysfunction.27,28

Chronic Low-Grade Inflammation

PMOS patients exhibit a state of systemic chronic low-grade inflammation, characterized by elevated serum levels of inflammatory markers, including white blood cell count, C-reactive protein, interleukin-6 (IL-6), interleukin-18, tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1.27–29 Inflammatory marker levels in PMOS patients are positively correlated with the degree of IR, the severity of HA, and body mass index.30–32 Obesity is a significant contributor to inflammation activation, as adipose tissue secretes abundant pro-inflammatory cytokines.33,34 These cytokines participate in PMOS pathology through several mechanisms. They interfere with post-insulin receptor signaling pathways and insulin receptor substrate 1-phosphatidylinositol 3-kinase-protein kinase B (IRS1-PI3K-AKT) pathway, inhibiting insulin signal transduction and inducing IR.35 They also stimulate ovarian stromal cells to secrete androgens, aggravating HA. Furthermore, they directly impair ovarian granulosa cell function, inhibiting follicular development and ovulation.

OS and ROS

OS refers to a state where excessive reactive oxygen species (ROS) are produced or antioxidant defense systems are weakened, leading to ROS accumulation and cellular damage. PMOS patients exhibit significantly elevated serum ROS levels and reduced activity of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase, indicating an imbalance between oxidation and antioxidation.36,37 OS is intimately linked with chronic inflammation. Inflammation can promote ROS generation through pathways like NADPH oxidase activation,38 while ROS, in turn, can activate signaling pathways such as nuclear factor-κB (NF-κB), NOD-like receptor protein 3 inflammasome, and activator protein-1, thereby promoting the release of inflammatory factors and exacerbating the inflammatory response.39,40 The pathological effects of OS in PMOS primarily include damage to ovarian granulosa cell mitochondrial function, leading to energy metabolic disorders and inhibited follicular maturation. It also causes oxidative damage to DNA, affecting ovarian cell proliferation and differentiation, and aggravates IR, forming a detrimental inflammation-OS-IR vicious cycle.41 The synergistic action of inflammation, OS, and IR creates a complex and self-sustaining pathological loop that drives the progression of PMOS.

Mitochondrial Dysfunction and Gut Microbiota Dysbiosis

Recent research has shed light on the crucial roles of mitochondrial dysfunction and gut microbiota dysbiosis as emerging pathological factors in PMOS.

Mitochondrial Dysfunction in Ovarian and Metabolic Tissues

Mitochondrial dysfunction plays a significant role in the pathogenesis of PMOS, with significant structural and functional abnormalities observed in ovarian granulosa cells, adipose tissue, and skeletal muscle cells.42,43 These abnormalities include a reduction in mitochondrial number, irregular morphology, increased mtDNA mutation rates, and impaired ATP production.44 Such dysfunction disrupts energy metabolism, hindering granulosa cell proliferation and differentiation, thus contributing to follicular arrest.45 Moreover, impaired mitochondrial respiration leads to excessive ROS generation, exacerbating OS and ovarian damage.46 Mitochondrial dysfunction in skeletal muscle and adipose tissue further promotes IR by impairing glucose uptake and utilization.47 Notably, lower mtDNA copy numbers in ovarian granulosa cells of PMOS patients correlate with reduced insulin sensitivity and elevated androgen levels, underscoring mitochondrial dysfunction as a key pathological feature of PMOS.48

Gut Microbiota Dysbiosis

The gut microbiota plays a significant role in PMOS pathogenesis. It maintains homeostasis by regulating nutrient metabolism, short-chain fatty acid synthesis, and immune function.49,50 In PMOS, dysbiosis is marked by an increased Firmicutes/Bacteroidetes ratio, reduced beneficial bacteria, and increased opportunistic pathogens.49 These changes contribute to PMOS through several mechanisms: increased Firmicutes abundance promotes nutrient absorption, leading to obesity and IR;51 reduced beneficial bacteria impair short-chain fatty acid production, exacerbating IR;52 and dysbiosis disrupts intestinal barrier function, triggering endotoxin translocation, systemic inflammation, and reinforcing the inflammation-IR cycle.53,54 Additionally, gut microbiota influences estrogen metabolism through the enterohepatic circulation, and dysbiosis leads to estrogen imbalance, affecting HPO axis function.55,56

Genetic and Environmental Influences

PMOS is a complex disorder where genetic susceptibility interacts with environmental factors to trigger disease onset.

Genetic Predisposition and Epigenetic Modifications

PMOS exhibits a clear familial aggregation, with first-degree relatives of PMOS patients having a significantly higher risk of developing the condition; daughters face a five-fold increased risk compared to their peers, while sons are at higher risk for obesity and dyslipidemia.57,58 The inheritance pattern of PMOS is not Mendelian but rather a result of polygenic interactions. Large-scale genome-wide association studies have identified 19 susceptibility loci significantly associated with PMOS risk,59 many of these susceptibility loci are shared between Han Chinese and European populations, suggesting a common genetic basis for PMOS.57

Epigenetic modifications serve as a crucial bridge between genetics and environment, playing a key role in PMOS pathogenesis. Epigenetic mechanisms regulate gene expression without altering the DNA sequence and are heritable Studies have revealed multiple differentially methylated genes in ovarian granulosa cells and adipose tissue of PMOS patients,60,61 such as hypomethylation in the promoter regions of CYP19A1 and SHBG genes, leading to abnormal expression and consequently affecting estrogen synthesis and androgen binding.62

Environmental Endocrine Disruptors and Lifestyle Factors

The genetic susceptibility of PMOS requires interaction with environmental factors for disease manifestation, with lifestyle, endocrine-disrupting chemicals, and obesity being the most critical environmental contributors.63 Lifestyle factors include diet, exercise, and sleep. High-sugar and high-fat diets can induce IR, exacerbate HA symptoms, and promote fat accumulation by elevating blood glucose and activating insulin secretion.64 Lack of exercise leads to energy metabolic imbalance, increasing the risk of obesity and IR.65 Sleep disorders can disrupt melatonin secretion and activate the hypothalamic-pituitary-adrenal axis, leading to hormonal imbalances and worsening PMOS symptoms.63 Clinical studies show that lifestyle interventions, such as a low-sugar, low-fat diet and regular exercise, can restore ovulation in 30–50% of PMOS patients and improve IR and inflammation.66

Endocrine-disrupting chemicals, including bisphenol A (BPA), phthalates, and triclosan, interfere with endocrine function and contribute to PMOS pathogenesis.67 BPA, a common endocrine-disrupting chemical, exhibits estrogen-like activity and contributes to PMOS pathogenesis by affecting ovarian morphology, interfering with the activity of steroidogenic enzymes (CYP17A1, CYP19A1), and damaging follicular development.68,69 Studies have found significantly higher BPA levels in PMOS patients compared to healthy women, with BPA levels positively correlating with testosterone levels; prolonged BPA exposure can also induce IR.70 Other environmental pollutants like microplastics may similarly heighten PMOS risk.14

TCM Understanding of PMOS

TCM approaches PMOS from a holistic perspective, recognizing it as a complex condition stemming from a combination of congenital predispositions and acquired imbalances (Figure 2). While PMOS does not have a direct equivalent name in TCM, its clinical manifestations, such as menstrual irregularities, infertility, hirsutism, and acne, are categorized under various TCM disease entities like amenorrhea, infertility, and masses in the abdomen. The fundamental TCM pathogenesis of PMOS centers on the dysfunction of the kidney-tiangui-chong-ren-baogong axis, with imbalances in the liver, spleen, and kidney organs ultimately leading to the endogenous generation of phlegm and blood stasis, which then obstruct the uterus and manifest as disease.71 Clinically, PMOS often presents as complex syndromes rather than single patterns.

Figure 2.

The pathogenesis of PMOS from TCM perspective.

Core Pathogenesis: Dysfunction of the Kidney-Tiangui-Chong-Ren-Baogong Axis

The kidney is considered the root of congenital essence, storing essence and governing reproduction. A robust kidney essence is a prerequisite for the timely arrival of tiangui, a substance related to reproductive maturation, the smooth flow of the chong and ren meridians, and normal follicular development and ovulation. As stated in Jing Yue Quan Shu, Delayed menstruation is due to blood deficiency, blood deficiency is due to kidney deficiency, highlighting the link between kidney deficiency and menstrual disorders. The kidney deficiency pathogenesis in PMOS primarily manifests as kidney yin deficiency and kidney yang deficiency, which often influence each other. Kidney yin deficiency, stemming from congenital insufficiency or acquired depletion, leads to inadequate nourishment by kidney yin, resulting in delayed follicular development and failure to form dominant follicles. Professor Xia Guicheng proposed that kidney yin is the material basis for oocyte growth and development and the driving force for menstrual cycle evolution, suggesting that kidney yin deficiency and immature essence-oocytes are fundamental to PMOS pathogenesis. Conversely, kidney yang deficiency impairs qi transformation and water metabolism, promoting fluid retention and the formation of phlegm-dampness, which can further affect spleen yang and exacerbate internal damp accumulation. Clinically, these pathological factors are associated with obesity, impaired qi and blood circulation, and the formation of blood stasis, ultimately disrupting the chong and ren meridians and leading to menstrual irregularities and infertility.19 Professor Luo Songping noted that imbalance and disharmony of kidney yin and yang are the fundamental reasons for the complex clinical manifestations of PMOS, with clinical presentations often including complex syndromes like kidney deficiency with phlegm-dampness and kidney deficiency with blood stasis.

Key TCM Syndromes and Their Pathological Manifestations

Kidney Deficiency

Kidney deficiency, encompassing both yin and yang aspects, is a foundational pattern in PMOS. It directly impacts reproductive function by affecting follicular development and hormonal balance, and indirectly contributes to metabolic disturbances through its influence on water metabolism and overall vitality.

Spleen Deficiency with Phlegm-Dampness

In TCM, the spleen governs transportation, transformation, and blood production, and its dysfunction is central to the pathogenesis of PMOS. Spleen deficiency is commonly associated with long-term intake of rich, sweet, greasy, cold, and raw foods, which impairs spleen yang and disrupts fluid metabolism, leading to phlegm-damp accumulation and obesity, particularly in the abdominal region. Emotional stress may induce liver qi stagnation, which further impairs spleen function and exacerbates phlegm-damp formation. Deficient spleen function results in insufficient qi and blood production, failing to nourish the sea of blood, thereby contributing to menstrual irregularity or amenorrhea. Spleen dysfunction may also affect blood regulation, leading to abnormal uterine bleeding.72

Phlegm-dampness is a key pathogenic factor in PMOS,73 obstructing the chong and ren meridians and impairing ovulation, thereby contributing to infertility. Its interaction with blood stasis further aggravates disease progression.74 Clinically, the spleen deficiency with phlegm-dampness pattern is characterized by obesity, fatigue, leukorrhea, and menstrual disorders, and is closely associated with IR. For spleen deficiency with phlegm-dampness type PMOS, formulas like Cangfu Daotan Wan are commonly used to invigorate the spleen, eliminate dampness, transform phlegm, and unblock meridians, which can significantly improve metabolic indicators and ovulatory function.75,76

Liver Qi Stagnation and Blood Stasis

In TCM, the liver governs the smooth flow of qi and stores blood, playing a key role in regulating ovulation and menstrual cycles through coordination with kidney qi. Emotional stress is a primary trigger of liver stagnation in PMOS.77

Liver qi stagnation disrupts qi and blood circulation, leading to blood stasis and obstruction of the chong and ren meridians, manifested as menstrual irregularity, amenorrhea, and dysmenorrhea. Prolonged stagnation may transform into heat, injuring kidney yin and further disturbing the chong and ren vessels, thereby aggravating reproductive dysfunction. In addition, liver dysfunction may impair spleen function, promoting phlegm-damp accumulation and contributing to a combined pathological pattern. Through inter-organ relationships, liver pathology may also affect the heart–kidney axis, resulting in endocrine imbalance and reduced fertility. Clinically, formulas like Chaihu Shugan San combined with Taohong Siwu Tang are often used to soothe the liver, regulate qi, activate blood, and resolve stasis, which can improve HA symptoms and ovulatory function.

Phlegm-Stasis Intertwining

In TCM, phlegm–stasis intertwinement is a key pathological feature of advanced PMOS and underlies its chronic and refractory course. A bidirectional relationship exists between phlegm and blood stasis: phlegm-dampness obstructs qi and blood flow, leading to blood stasis, while blood stasis further disrupts qi movement and water metabolism, promoting phlegm formation and forming a self-perpetuating cycle. Obstruction of the uterine axis aggravates ovulatory dysfunction, menstrual irregularities, and infertility, and may increase the risk of endometrial hyperplasia and uterine fibroids.

Clinically, PMOS patients with phlegm-stasis intertwining often present with obesity, delayed menstruation or amenorrhea, dysmenorrhea, dark and clotted menstrual blood, dark purple tongue or with petechiae, and wiry-thready or choppy pulse. Serum inflammatory cytokine levels are significantly higher in these patients compared to those with single syndromes, indicating an association with chronic low-grade inflammation. For phlegm-stasis intertwining type PMOS, formulas that transform phlegm and activate blood are commonly used, which can reduce inflammatory cytokine levels and improve IR and ovulatory function.

To systematically organize and clarify the TCM theories involved in PMOS and their corresponding modern medical explanations, Table 1 summarizes TCM concepts and their underlying biomedical interpretations to help readers better understand the TCM theoretical framework.

Table 1.

TCM Concepts Involved in PMOS and Their Potential Biomedical Interpretations

TCM concept	Traditional Definition	Possible Biomedical Correlate
Kidney–tiangui–chong–ren–baogong axis	Functional reproductive regulatory network	HPO axis, ovarian endocrine regulation, uterine physiology
Tiangui	Reproductive maturation	Sex hormone regulation
Chong and ren meridians	Menstrual regulation	Neuroendocrine reproductive regulation
Kidney deficiency	Impaired reproductive essence	Ovarian dysfunction, endocrine imbalance
Spleen deficiency	Impaired digestive and metabolic function in TCM	Metabolic dysfunction, IR, gut microbiota dysbiosis
Phlegm-dampness	Accumulation of pathological fluids	Obesity, IR, dyslipidemia
Blood stasis	Impaired blood circulation	Chronic inflammation, endothelial dysfunction, impaired microcirculation
Liver qi stagnation	Emotional and qi dysregulation	Stress-related neuroendocrine dysfunction
Baogong	Female reproductive organ in TCM	Uterus and female reproductive system
Spleen deficiency with phlegm-dampness	Impaired digestive function with phlegm-dampness accumulation	Obesity, IR, dyslipidemia, metabolic syndrome
Liver qi stagnation and blood stasis	Emotional dysregulation accompanied by impaired blood circulation	Neuroendocrine dysfunction, chronic inflammation, endothelial dysfunction, impaired microcirculation
Phlegm-stasis intertwining	Concurrent accumulation of phlegm-dampness and blood stasis	Metabolic dysfunction, ectopic lipid accumulation, chronic inflammation, OS, microvascular dysfunction

Natural Products in PMOS Treatment

Natural products, with their diverse chemical constituents and multi-target pharmacological activities, offer a compelling therapeutic avenue for PMOS and its associated comorbidities. Their mechanisms of action often span multiple pathological pathways, providing a holistic approach that aligns well with the complex nature of PMOS. As illustrated in Figure 3, this section systematically reviews the current understanding of how natural products intervene in PMOS, integrating both western medical and TCM perspectives.

Figure 3.

Mechanisms underlying the treatment of PMOS with natural products. Reactive oxygen species (ROS); interleukin-6 (IL-6); tumor necrosis factor-α (TNF-α); sirtuin 3 (SIRT3); phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt); nuclear factor-κB (NF-κB)/IκB kinase (IκK); insulin receptor substrate 1 (IRS-1).

Modulating Glucose Metabolism and Insulin Sensitivity

Glucose metabolic abnormalities, primarily driven by IR and pancreatic β-cell dysfunction, are pivotal in PMOS pathogenesis.78 Furthermore, in PMOS women, OS and inflammatory responses induced by IR are major contributors to β-cell damage, reducing chronic inflammation is crucial for improving glucose metabolism.11 Natural products demonstrate significant potential in ameliorating these dysfunctions.

Targeting PI3K/Akt and NF-κB Pathways

Several natural compounds exert their beneficial effects on glucose metabolism by modulating key signaling pathways. Quercetin, a widely distributed flavonoid, has well-established glucose-regulating activity. It upregulates Sirtuin 3 (SIRT3) expression, enhancing cellular antioxidant capacity, mitigating IR-induced OS, and inhibiting pancreatic β-cell apoptosis.79 This ultimately improves insulin secretion and sensitivity, thereby alleviating glucose metabolic disorders in PMOS patients. Curcumin, the active component of Curcuma longa, aligns with the TCM concept of activating blood and resolving stasis in PMOS. Modern pharmacological studies confirm its role in glucose metabolism.80 Curcumin activates the PI3K/Akt signaling pathway, regulating the expression of key hepatic glucose metabolic enzymes and inhibiting excessive hepatocyte apoptosis, thus improving hepatic IR. In PMOS models, curcumin significantly reduces blood glucose levels, improves IR and HA, likely through PI3K/Akt pathway-mediated synergistic regulation of glucose and lipid metabolism, offering comprehensive intervention for PMOS endocrine-metabolic disorders.81,82 Leonurine, a characteristic alkaloid from Leonurus japonicus, improves PMOS glucose metabolic abnormalities through synergistic anti-inflammatory and hypoglycemic actions.83 It inhibits the NF-κB/IκK pathway, reducing IR-induced chronic inflammation. Concurrently, it restores the transcriptional balance of key hepatic glucose metabolic enzymes via Akt-dependent pathways, significantly lowering PMOS-related hyperglycemia and increasing plasma insulin concentrations.83 This positions leonurine as a promising natural active molecule for PMOS glucose metabolic intervention.

Protecting Pancreatic β-Cells and Regulating Glucose Metabolism-Related Enzymes

Protecting pancreatic β-cell function from oxidative damage is crucial for maintaining glucose homeostasis. Quercetin’s ability to upregulate SIRT3 contributes to its protective effects on β-cells by enhancing antioxidant defenses.79 Berberine, while primarily known for its effects on HA, also improves insulin sensitivity and glucose metabolism, partly by reducing OS and inflammation that can damage β-cells.84 Tanshinone I, a major lipophilic active component of Salvia miltiorrhiza, modulates insulin signaling pathways to improve PMOS glucose metabolic disorders.85 It reduces levels of IL-6 and TNF-α, inhibits NF-κB nuclear translocation, and mitigates inflammation-mediated insulin signaling damage. Furthermore, it reduces Ser307 phosphorylation of Insulin Receptor Substrate 1 (IRS-1), restoring IRS-1-mediated insulin signaling efficiency, thereby improving IR and lowering blood glucose levels.85 This provides experimental evidence for natural products targeting insulin signaling pathways in PMOS treatment.

Regulating Lipid Metabolism and Preventing Cardiovascular Disease

Dyslipidemia is another hallmark of PMOS, it interacts synergistically with IR, thereby exacerbating disease progression.86,87 Natural products, with their hypolipidemic, anti-inflammatory, and antioxidant activities, offer unique advantages in regulating PMOS lipid metabolism.

Reducing Hyperlipidemia and Inhibiting Lipid Peroxidation

Cinnamon, traditionally used as a warming herb, has a pungent, sweet, and hot nature that aligns with TCM patterns like spleen and kidney yang deficiency with phlegm-dampness retention. Modern pharmacological studies confirm its anti-inflammatory, antioxidant, hypolipidemic, and insulin-sensitizing effects.88 A meta-analysis demonstrated that cinnamon reduces body weight, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels, while also improving IR and fasting blood glucose, thereby disrupting the IR-dyslipidemia vicious cycle and alleviating PMOS-related metabolic abnormalities.89 Aloe Vera, with both medicinal and edible value, contains various active components that synergistically regulate glucose and lipid metabolism.90 Animal studies by Dey et al showed that aloe vera gel and extracts directly target dyslipidemia and IR in PMOS mice, significantly reducing body weight, plasma triglycerides (TG) levels, and IR index. It also reversed arrested estrous cycles, abnormal glucose tolerance, and dysregulated steroid hormone-related gene expression.91 Its mechanism may involve indirectly regulating ovarian steroid hormone synthesis by improving lipid metabolic homeostasis, achieving simultaneous intervention in PMOS metabolic abnormalities and reproductive dysfunction. Camellia Fruit Extract improves PMOS dyslipidemia primarily by inhibiting lipid peroxidation. Lee et al found that camellia fruit extract significantly modulated the lipid profile in hypercholesterolemic rats, reducing TC, TG and LDL-C levels while increasing high-density lipoprotein cholesterol (HDL-C). It also reduced serum lipid peroxidation levels by inhibiting thiobarbituric acid reactive substance formation and decreased arterial lipid deposition.92 This mechanism aligns well with the OS damage accompanying PMOS dyslipidemia, suggesting its potential as an herbal intervention for PMOS dyslipidemia through synergistic hypolipidemic and antioxidant effects. Emodin, a widely present anthraquinone in herbs like Rheum officinale and Polygonum cuspidatum, multi-targetedly regulates lipid metabolism and vascular endothelial function to improve PMOS pathological states.93 Studies show that emodin significantly improves dyslipidemia in high-cholesterol diet-fed rats, reducing serum TC and LDL-C levels. It also enhances antioxidant capacity and restores aortic endothelial function, mitigating lipid peroxidation and endothelial damage to metabolic homeostasis.94 Its mechanisms, involving hypolipidemic, antioxidant, and endothelial-protective effects, closely match the OS and vascular endothelial dysfunction associated with PMOS dyslipidemia, thus breaking the vicious cycle of PMOS metabolic disorders.

Improving Autophagy and Modulating AMPK and PPAR Pathways

Ginsenoside Rb1, a major active component of Panax ginseng, intervenes in PMOS-related dyslipidemia by regulating autophagy. Ginseng, a traditional medicine for metabolic diseases, and its saponin Rb1, are known to promote lipid metabolism and inhibit lipid accumulation.95 Qiao ‘s in vitro and in vivo experiments demonstrated that Rb1 promotes AMP-activated protein kinase (AMPK) phosphorylation in atherosclerotic plaques, inducing macrophage autophagy and reducing lipid accumulation in foam cells.96 This mechanism directly targets core aspects of PMOS dyslipidemia, ectopic deposition, and inflammatory cell infiltration, providing a new mechanistic reference for natural products targeting lipid metabolism-inflammation pathways in PMOS. Icariin, the core flavonoid active component of Epimedium brevicornu, alleviates PMOS metabolic abnormalities by regulating key steps in lipid metabolism. Yan et al showed that Epimedium aqueous extract significantly reduces serum TC and TG levels in women, improving dyslipidemia.97 Based on PMOS pathological features, it is hypothesized that icariin may regulate the activity of enzymes involved in adipocyte lipid synthesis and breakdown, improve lipid metabolic homeostasis, and simultaneously alleviate IR, thereby reducing the adverse effects of dyslipidemia on ovarian function and intervening in PMOS.98 Dihydromyricetin (DHM), a flavonoids, DHM has a wide range of biological and pharmacological functions in regulating glucose and lipid metabolism.99 DHM influences lipid homeostasis via sterol regulatory element binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor (PPAR).100 Research findings indicate that via the phosphorylation at the Thr172 site, DHM activated AMPK to generate lipid metabolic responses, and then decreased the lipid in blood.101 Consequently, DHM regulates lipid metabolism and helps prevent cardiovascular disease by modulating the PPAR and AMPK pathways.

Restoring Hormonal Balance and Ameliorating HA

HA is one of the key pathological features of PMOS. Its primary cause is an abnormal response of the ovaries to gonadotropin-releasing hormone, leading to excessive local androgen synthesis in the ovaries,26 which in turn causes ovulatory dysfunction and exacerbates endocrine and metabolic imbalances. Natural products demonstrate clear targeted advantages in modulating HA.

Inhibiting Ovarian Androgen Synthesis and Regulating Gonadotropin Receptors

Artemisinins have been shown by Liu et al to directly bind to lon peptidase 1 (LONP1), enhancing its interaction with cytochrome P450 family 11 subfamily A member 1 (CYP11A1), promoting CYP11A1 degradation, and thus inhibiting ovarian androgen synthesis at the source. This significantly improves HA and polycystic ovarian morphology, while restoring normal menstrual cycles.102 This mechanism provides a clear molecular target for natural products precisely intervening in PMOS via androgen synthesis pathways. Berberine, as a core alkaloid from Coptis chinensis and Phellodendron chinense, has a bitter and cold nature that aligns with the damp-heat accumulation TCM pattern common in PMOS HA.103 Modern pharmacological research confirms that berberine upregulates LH/CG-R and CYP19A1 protein and mRNA expression in ovarian tissue, promoting androgen-to-estrogen conversion. It also downregulates integrin αvβ3 and lysophosphatidic acid receptor 3 expression, improving endometrial receptivity. Its core action primarily involves regulating sex hormone balance and ameliorating HA-mediated reproductive system damage.103

Improving Ovarian Microenvironment and Modulating Androgen Receptor Signaling

Resveratrol, widely found in Polygonum cuspidatum and grapes, has a slightly cold nature and ability to clear heat, resolve dampness, dissipate stasis, and detoxify, aligning with the blood stasis and heat intertwining pathological state in PMOS.104 Its core mechanism for improving HA is closely related to ovarian function repair. Chen et al showed that resveratrol elevates cytoplasmic calcium concentration in PMOS rats, promoting excessive phosphorylation of calcium-/calmodulin-dependent protein kinase II β (CaMKIIβ), repairing transzonal projections in ovarian tissue, and reversing ovarian failure and estrous cycle disorders.104 It also indirectly balances androgen levels by activating the MAPK/ERK signaling pathway to regulate estrogen metabolism, mitigating HA-induced damage to endometrial receptivity.105 This achieves synergistic intervention in PMOS HA and related reproductive dysfunction. Tribulus terrestris and its compound preparations have been shown to directly increase ovulation frequency and reduce ovarian cyst volume in PMOS patients, likely by regulating the gonadal axis.82 Saiyed et al further confirmed that a compound extract of Withania somnifera and Tribulus terrestris elevates FSH levels and reduces LH and testosterone levels in PMOS rats, regulating gonadal axis hormone balance. It also reverses abnormal ovarian and uterine weights and ovarian structural disorders,106 improving HA at the source and providing experimental evidence for compound natural product intervention in PMOS. Dendrobium Polysaccharides primarily protect ovarian follicular development, indirectly improving HA-mediated ovarian dysfunction. Zhang et al showed that Dendrobium polysaccharides restore disordered estrous cycles in PMOS rats by reducing antral follicle count, increasing granulosa cell layer thickness, and inhibiting ovarian tissue cell apoptosis, thereby improving abnormal follicular development.107 Its mechanism may involve repairing HA-damaged granulosa cell function, which promotes follicular maturation, breaks HA’s inhibition of follicular development, and indirectly regulates sex hormone balance, alleviating PMOS pathological states.107 Curcumin precisely regulates HA by targeting the Wnt signaling pathway to downregulate androgen receptor expression, inhibiting HA-mediated abnormal endometrial proliferation. It also modulates androgen signaling to reduce the adverse effects of HA on the ovaries and reproductive system.108

To systematically collate and clarify the diverse mechanisms by which natural products exert therapeutic effects on PMOS and its comorbidities, the key pathways, target molecules, and corresponding natural product candidates are summarized in Table 2, providing a concise and intuitive reference for the current research progress in this field.

Table 2.

Summary of Mechanisms Underlying the Use of Natural Products to Improve Metabolism in the Treatment of PMOS

Natural Product	Primary Therapeutic Target	Main Mechanisms	Biological Outcomes	Ref
Quercetin	Glucose metabolism	Activates SIRT3; enhances antioxidant defense; regulates PI3K/Akt and Nrf2 pathways; inhibits β-cell apoptosis	Improves IR; enhances insulin secretion; reduces OS	[79]
Curcumin	Glucose metabolism and hormones	Activates PI3K/Akt signaling; regulates Wnt pathway and androgen receptor; modulates glucose–lipid metabolism	Lowers blood glucose; improves IR; alleviates HA	[81,82,108]
Leonurine	Glucose metabolism	Inhibits NF-κB/IκK pathway; regulates Akt-dependent glucose metabolism enzymes	Reduces chronic inflammation; improves hyperglycemia and IR	[83]
Berberine	Glucose metabolism and hormones	Modulates insulin signaling; upregulates CYP19A1 and LH/CG-R; reduces OS	Improves IR; promotes androgen-to-estrogen conversion; ameliorates HA	[84,103]
Tanshinone I	Glucose metabolism	Inhibits NF-κB signaling; reduces IRS-1 Ser307 phosphorylation; restores insulin signaling	Improves insulin sensitivity; reduces blood glucose	[85]
Cinnamon	Lipid metabolism	Anti-inflammatory and antioxidant; improves insulin signaling and lipid metabolism	Reduces body weight, TC, LDL-C; improves IR and glucose metabolism	[88,89]
Aloe vera	Lipid metabolism	Regulates glucose–lipid metabolism; modulates steroid hormone-related gene expression	Reduces TG, body weight; restores estrous cycle; improves IR	[90,91]
Camellia fruit extract	Lipid metabolism	Inhibits lipid peroxidation; regulates lipid metabolism	Reduces TC, TG, LDL-C; increases HDL-C; protects vascular endothelium	[92]
Emodin	Lipid metabolism	Regulates lipid metabolism; antioxidant; improves endothelial function	Reduces TC, LDL-C; alleviates lipid peroxidation and vascular damage	[93,94]
Ginsenoside Rb1	Lipid metabolism	Activates AMPK; induces autophagy; reduces foam cell lipid accumulation	Improves dyslipidemia; reduces lipid deposition and inflammation	[95,96]
Icariin	Lipid metabolism	Regulates lipid metabolism enzymes; improves metabolic homeostasis	Reduces TC and TG; alleviates IR and lipid disorders	[97,98]
Dihydromyricetin	Lipid metabolism	Modulates SREBP-1c and PPAR; activates AMPK	Lower blood lipids; regulate lipid homeostasis	[99–101]
Artemisinin	Hormones	Targets LONP1–CYP11A1 axis; inhibits androgen synthesis	Reduces androgen levels; improves ovarian morphology and menstrual cycle	[102]
Resveratrol	Hormones	Activates MAPK/ERK; regulates CaMKIIβ signaling; improves ovarian microenvironment	Restores ovarian function; reduces HA; improves endometrial receptivity	[104,105]
Tribulus terrestris	Hormones	Regulates hypothalamic–pituitary–gonadal axis	Increases ovulation; reduces ovarian cysts; balances hormones	[82,106]
Dendrobium polysaccharides	Hormones	Protects granulosa cells; inhibits apoptosis; promotes follicular development	Restores estrous cycle; improves follicular maturation	[107]

Challenges and Future Directions

Despite the promising potential of natural products in PMOS research, their journey from laboratory findings to widespread clinical application is fraught with significant challenges. The primary bottleneck lies in the disconnect between basic research and clinical translation. Addressing these issues requires a multi-dimensional approach, systematically exploring avenues to overcome current barriers.

Elucidating the Material Basis and Synergistic Mechanisms of Natural Products

The inherent complexity of natural products, particularly TCM formulas, presents a major hurdle. The precise identification and quantification of effective compound groups within multi-component natural product extracts remain largely undefined. It is often the synergistic action of multiple components, rather than a single active ingredient, that confers therapeutic efficacy. Future research must employ advanced analytical techniques coupled with bioactivity-guided fractionation to systematically characterize the active constituents. Furthermore, the molecular mechanisms underlying the synergistic enhancement among multiple components are poorly understood. This lack of in-depth mechanistic elucidation limits the precise identification of intervention targets and hinders the scientific validation required for clinical precision medicine. Network pharmacology, systems biology, and computational modeling approaches should be leveraged to map the complex interactions between natural product components, their multiple targets, and the intricate pathological pathways of PMOS. This will help to elucidate how these compounds collectively modulate key signaling networks.

Strengthening Evidence-Based Medicine

The current evidence base for natural products in PMOS treatment is often considered weak, primarily due to a reliance on preclinical studies. Most studies are still confined to in vitro or animal experiments, with a scarcity of large-sample, long-term, multi-center randomized controlled trials. This deficiency prevents adequate validation of the clinical efficacy, long-term safety, and dose-response relationships of natural products, thereby impeding their widespread clinical adoption. Future research must prioritize rigorous clinical trial designs to generate robust evidence. Additionally, establishing standardized protocols for evaluating clinical outcomes and adverse events is crucial. This includes developing universally accepted endpoints, validated assessment tools, and comprehensive safety monitoring frameworks specifically tailored for natural product interventions in PMOS.

Advancing Translational Research

Translational research in natural products for PMOS is relatively lagging, particularly concerning the optimization of effective components. Many natural active ingredients suffer from poor physicochemical properties, such as low solubility, poor stability, and low bioavailability, which significantly limit their clinical utility. Research should focus on structural modifications to enhance their pharmacological profiles and developing novel drug delivery systems. Given the emerging role of gut microbiota in PMOS, the development of targeted microecological preparations derived from or inspired by natural products, holds significant promise. These could specifically modulate the gut microbiota composition and function to alleviate PMOS symptoms. Nanocarriers, targeted delivery systems, and other advanced pharmaceutical technologies can improve the bioavailability and targeting of active components, thereby enhancing the efficiency and quality of clinical translation.

Deepening Interdisciplinary Research

Breaking down traditional disciplinary silos is essential for future breakthroughs. Integrating multi-omics technologies, such as genomics, transcriptomics, proteomics and metabolomics, is crucial to systematically decipher the core effective component groups and key signaling pathways of natural products in PMOS. This will clarify the precise component-target-pathological link relationships. Furthermore, research should investigate the specific pathways through which active components of TCM exert epigenetic regulation. This will provide a deeper understanding of the molecular mechanisms underlying different PMOS syndromes. Artificial intelligence and machine learning algorithms can accelerate the discovery of novel natural product candidates, predict their efficacy and toxicity, and optimize treatment regimens. Artificial intelligence -driven approaches can also aid in developing personalized treatment strategies based on individual patient profiles, including genetic background, TCM syndrome, and gut microbiota composition.

Establishing a Comprehensive PMOS Health Management System

A holistic approach to PMOS management extends beyond pharmacological interventions. Developing comprehensive health management systems that integrate lifestyle modifications with TCM body constitution conditioning programs is vital. This approach emphasizes prevention and long-term well-being. Fostering closer collaboration between basic scientists, clinicians, and pharmaceutical developers is essential to translate research findings into practical clinical applications. This includes establishing platforms for knowledge exchange, joint research initiatives, and streamlined regulatory pathways for natural product-based therapies.

Conclusion

In conclusion, the integration of western medicine and traditional Chinese medicine reveals that PMOS is a complex network of metabolic and endocrine imbalances rather than a collection of isolated symptoms. Natural products, with their multi-target properties, offer a unique advantage over conventional drugs by simultaneously improving glucose-lipid metabolism and restoring hormonal balance. Future research should move toward precision ethnopharmacology by combining traditional wisdom with modern technologies like multi-omics and advanced drug delivery systems. This approach will help develop personalized, evidence-based therapies that address the root causes of PMOS, ultimately providing safer and more effective clinical solutions for women worldwide.

Disclosure

The authors report no conflicts of interest in this work.