Oxidative stress and the therapeutic potential of dietary antioxidants in polycystic ovary syndrome: a narrative review

Abstract

It is becoming more well acknowledged that oxidative stress is a crucial component that connects the hormonal, metabolic, and reproductive aspects of polycystic ovarian syndrome (PCOS). A more holistic and natural approach to managing the illness might be possible through lowering this disparity. This review outlines new findings about the effects of dietary antioxidants on critical processes related to PCOS, such as insulin signaling, inflammation, and mitochondrial activity. Antioxidants that have demonstrated encouraging effects in reducing oxidative stress, insulin resistance, and ovulatory health include N-acetylcysteine, coenzyme Q10, α-lipoic acid, and vitamins C and E. However, it's challenging to draw definitive findings due to limited intervention periods and variances in the study's methodology. More thorough, deeper, and more extensive standardized trials should be the main emphasis of future studies. Taken together, the results indicate that dietary antioxidants have significant medicinal value to help women with PCOS regain redox equilibrium and enhance their overall metabolic and reproductive health.

Introduction

A prevalent and complicated endocrine-metabolic condition, PCOS affects 8–13% of women globally who are of reproductive age. Though the clinical manifestation varies greatly from person to person, it is typified by polycystic ovarian morphology, hyperandrogenism, and ovulatory malfunction. PCOS's systemic and multifactorial aspect is highlighted by its substantial correlations with insulin resistance, corpulence, type 2 diabetes, lipid abnormalities, and a greater likelihood of cardiovascular disorders, in addition to its reproductive characteristics [20, 61].

PCOS displays a significant genetic component, with familial clustering and heritability projections indicating a higher inherited risk. Emerging data suggest that genetic predisposition interacts with metabolic dysfunction and chronic low-grade inflammation, both of which are now known to be key factors in the onset and progression of PCOS. Females with PCOS regularly show higher inflammatory markers and shifted metabolic profiles, suggesting the role of inflammation-associated agents and metabolites in disease development [63].

Furthermore, new studies emphasize the role of mitochondrial dysfunction and changes in mitochondrial DNA (mtDNA) in PCOS. Changes in mtDNA copy number, mutations, and epigenetic control which may be passed down via maternal inheritance—have been linked to decreased energy metabolism and elevated oxidative stress in PCOS. These mitochondrial disruptions offer a mechanistic connection between genetic susceptibility, metabolic dysregulation, and oxidative imbalance [64].

Based on previous studies, one of the main pathophysiological mechanisms behind the metabolic and reproductive abnormalities seen in PCOS is oxidative damage. When the human body's antioxidant defense capacity is exceeded by the generation of reactive oxygen species (ROS), oxidative stress takes place, resulting in cell destruction and malfunction [77]. Insulin resistance, hyperandrogenism, persistent low-level inflammation, and mitochondrial malfunctioning are some of the interrelated variables that lead to increased oxidative stress in PCOS. The pro-oxidative milieu generates a vicious loop that promotes the hallmarks and symptoms of the disease [93]. Due to their capacity to combat oxidative stress and the associated metabolic and reproductive disorders, dietary antioxidants are becoming increasingly popular in the treatment of polycystic ovary syndrome (PCOS). Both whole foods and isolated supplements can provide antioxidant exposure, and the biological context and clinical understanding of these two sources are different. Antioxidants can improve absorption and foster synergistic interactions with other nutrients when ingested as part of a regular diet because they are delivered within complex food matrices. Supplemental antioxidants, on the other hand, offer concentrated levels of particular compounds, which may result in more erratic and occasionally irregular clinical effects. Substances like vitamins, polyphenols, and trace elements have been demonstrated to effect inflammatory signaling, enhance insulin sensitivity, and support ovarian function in both experimental and practical contexts [137].

Since PCOS is multifactorial, changing one's lifestyle has become a key tactic for reducing oxidative stress and the pathophysiological effects that follow. Research indicates that using medicinal herbs, supplementing the diet with antioxidant-enhancing vitamins, and engaging in regular physical activity may boost endogenous antioxidant defenses and lessen the oxidative stress on the body [132].

Nevertheless, exercise is also linked to higher oxygen consumption, which, if not properly balanced, could result in brief increases in the generation of reactive oxygen species (ROS). On the other hand, relaxation techniques like yoga have been linked to lower oxygen consumption and notable drops in oxidative stress metrics. Furthermore, by modifying hypothalamic-pituitary-ovarian axis activity, yoga practices have been shown to normalize endocrine variables, enhancing fertility potential and lowering the likelihood of PCOS. These lifestyle-based techniques are becoming more widely acknowledged as complementary tactics to alleviate PCOS-related metabolic, inflammatory, and reproductive disorders [15, 108].

The therapeutic potential of dietary antioxidants in PCOS is supported by growing preclinical evidence demonstrating their ability to ameliorate oxidative stress markers, improve metabolic parameters, and restore reproductive function in animal models [127]. In clinical studies, cholecalciferol (vitamin D) supplementation in female with PCOS has been linked with enhancements in glucose metabolism, as well as decreases in estradiol amounts and triglyceride concentrations, suggesting positive metabolic and endocrine impacts. While some randomized controlled trials have shown promising effects of specific antioxidants on metabolic and reproductive outcomes in women with PCOS, translation to clinical practice requires careful evaluation of human studies, which have yielded mixed results. While some randomized controlled trials have shown promising effects of specific antioxidants on metabolic and reproductive outcomes in women with PCOS, others have failed to demonstrate significant benefits.

An increasing amount of preclinical research shows that dietary antioxidants can enhance metabolic balance, lower oxidative damage, and restore reproduction in animal studies, all of which indicate the curative value of these nutrients in PCOS [127]. These results imply that one effective method for reducing the complex pathophysiology of PCOS may be to focus on oxidative stress. An increasing amount of preclinical research shows that dietary antioxidants can enhance metabolic balance, lower oxidative stress, and restore reproductive function in animal models, all of which indicate the therapeutic potential of these nutrients in PCOS [127]. According to these results, reducing oxidative stress might be a good way to lessen the complex pathophysiology of PCOS. Nevertheless, the overall scientific evidence is still conflicting, despite the fact that a number of controlled experiments in women with PCOS have documented the positive benefits of certain antioxidants on metabolic, hormonal, and reproductive health. Therefore, careful analysis and more meticulously planned human trials are needed to confirm efficacy, the ideal dosage, and long-term safety before using these encouraging experimental findings in clinical settings.

Since PCOS is becoming more common and existing treatment methods are limited, it is especially important to comprehend how oxidative stress contributes to the disease and the possibility for antioxidant therapies. The primary goal of conventional PCOS care is to regulate symptoms with insulin sensitizers, hormonal contraceptives, and ovulation induction drugs; the underlying pathological processes are not addressed [38, 91]. A more focused approach to treating the core causes of PCOS may be possible with the incorporation of antioxidant techniques into overall care, which would also have additional metabolic and reproductive advantages. The goal of this narrative review is to integrate the most recent data regarding the role that oxidative stress plays in the onset and progression of PCOS and to evaluate the possible contribution of dietary antioxidants to its treatment. Through combining results from preclinical and clinical research, it aims to pinpoint the most promising antioxidants, elucidate regions where the data is still ambiguous, and highlight important areas for further investigation. The ultimate objective of this review is to offer information that will help inform evidence-based suggestions for integrating antioxidant therapy into the treatment of PCOS.

Oxidative stress as a pathogenic driver in PCOS

Mechanisms of ROS generation

Oxidative stress (OS) happens if the synthesis of reactive oxygen species (ROS), which are constantly produced as byproducts of regular aerobic metabolism and serve physiological signaling roles, surpasses the antioxidant defense systems. According to Muhammadi et al. [77], OS is characterized by a disparity among pro-oxidants and antioxidants, favoring the former and harming lipids, proteins, DNA, and organelles. Enzymatic oxidative networks, mitochondrial malfunction, and inflammatory cell engagement are the main biological sources of ROS in PCOS, and they all contribute to the escalation of oxidative damage in many tissue compartments [93] (Fig. 1).

Fig. 1.

Oxidative stress-induced mechanisms that lead to malfunction in the ovaries

Mitochondrial dysfunction

One of the main mechanisms generating oxidative stress in PCOS is mitochondrial malfunction, where increased superoxide production results from compromised electron transport chain activity. Ineffective mitochondrial oxidative phosphorylation (OXPHOS) in granulosa cells and peripheral tissues produces a cellular milieu that is marked by a decrease in ATP synthesis and a spike in ROS generation. Skeletal muscle tissue is the area where this mitochondrial impairment is most noticeable, since decreased respiratory complex activities and changed mitochondrial biogenesis led to both local as well as systemic oxidative load [36, 37]. According to emerging findings, PCOS patients commonly have epigenetic changes that impact mitochondrial gene expression as well as variations in mitochondrial DNA (mtDNA). According to Kobayashi et al. [64], these changes cause structural and functional anomalies in mitochondrial systems, which in turn cause electron leaking and the consequent generation of superoxide. A self-replicating loop of cellular dysfunction is produced by the oxidative harm that results, which impacts lipids, proteins, and DNA in ovarian cells and peripheral tissues [121].

Enzymatic ROS amplification systems

A significant part of ROS amplification in PCOS is played by the NADPH oxidase (NOX) family, especially NOX4. Higher androgen levels encourage the production of ROS, which worsens mitochondrial injury and more oxidative damage. This feed-forward loop is established when androgen-driven androgen receptor (AR) stimulation upregulates NOX4 expression in skeletal muscle and other peripheral tissues. By creating a pathological loop, this pathway effectively connects oxidative tissue impairment with hyperandrogenism [92, 130, 135]. In PCOS, xanthine oxidase is a further major enzymatic generator of reactive oxygen species. The blood and follicular fluid of PCOS individuals have been repeatedly found to have increased xanthine oxidase activity, which raises the systemic oxidant stress and total oxidant status (TOS). This enzyme is especially active when there is tissue hypoxia or metabolic strain, which are common in the hyperandrogenic and insulin-resistant environment of PCOS [50, 69].

Inflammatory cell activation and ROS production

Prolonged low-grade inflammation has been continously reported in women with PCOS and is characterized by higher circulating number of inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and C-reactive protein. Stimulation of inflammatory cells including macrophages and monocytes led to increased generation of reactive oxygen species (ROS), thereby enhancing oxidative burden [86, 94]. Women with PCOS are especially prone to establishing a persistent pro-inflammatory state, which is strongly linked with insulin resistance, elevated cardiovascular disease chance, and a variety of unfavorable metabolic and reproductive outcomes. This ongoing inflammatory environment interferes with insulin signaling processes and encourages metabolic dysfunction, which eventually leads to insulin resistance and reproductive abnormalities that are frequently seen in PCOS [26, 111].

When examining the relationship between PCOS and chronic inflammation, it is essential to consider the influence of elevated body mass index (BMI), as excess adiposity independently contributes to the upregulation of inflammatory mediators and oxidative stress. Adipose tissue–derived cytokines and the increased oxidative burden associated with higher BMI may therefore exacerbate the inflammatory phenotype observed in PCOS rather than act as primary causal factors. In this context, central obesity has emerged as a critical determinant of metabolic risk in PCOS [100]. The waist-to-height ratio (WHtR) has been proposed as a more sensitive anthropometric indicator than BMI for the early identification of insulin resistance and cardiometabolic risk in women with PCOS, as it more accurately reflects visceral fat accumulation and its associated inflammatory activity. Persistently high oxidative load due to long term inflammation has been linked with endothelial dysfunction and a higher probability of cardiovascular disease in women with PCOS. This highlights the interconnected links between inflammation, metabolic dysregulation, and chronic cardiometabolic risk [10].

Disruption of redox homeostasis and reproductive implications

Ovarian functioning is significantly impacted by redox balance disruption in PCOS. Granulosa cells' strong metabolic requirement and weak antioxidant responses make them more susceptible to oxidative injury. Poor oocyte quality and decreased fertilization potential result from ROS-induced damage, which also inhibits the generation of steroid hormones, encourages apoptosis, and interferes with communication within the cumulus-oocyte complex [65]. Additionally, oxidative damage modifies the ovary's extracellular matrix (ECM) remodeling. The thicker capsule characteristic of polycystic ovaries is caused by ROS's modification of collagen and other ECM proteins, which increases cross-linking and tissue stiffness. Follicle rupture and ovulation are additionally disrupted by irregular matrix metalloproteinases and their antagonists [104]. Oxidative stress impairs the production of the corpus luteum and the production of progesterone, which leads to luteal failure and decreased endometrial receptivity even after ovulation. Furthermore, oxidatively induced insufficient luteal vascularization lowers the possibility for implantation [2, 105].

Endocrine metabolic cross-talk

In PCOS, oxidative stress (OS) is a key unifying factor that connects metabolic dysregulation and endocrine irregularities. Redox disequilibrium maintains the hallmarks of insulin resistance (IR), hyperandrogenism, and anovulation by changing insulin signals, steroidogenesis, and vascular homeostasis. The ensuing feed-forward cycle intensifies oxidative damage on a local and systemic level.

Insulin resistance

In PCOS, insulin resistance is very common; even in lean phenotypes, it affects 35–80% individuals. Increased reactive oxygen species (ROS) cause molecular disruption of normal insulin signaling processes by triggering stress kinases including IκB kinase β (IKKβ) and c-Jun N-terminal kinase (JNK), which lead to serine phosphorylation of insulin receptor substrate-1 (IRS-1). According to Liu et al. [69], this alteration reduces glucose transporter (GLUT4) translocation and glucose uptake by blocking downstream PI3K/AKT stimulation. One of the main biological sources of ROS in insulin-sensitive tissues is mitochondrial malfunction. N-acetylcysteine administration improved decreased glutathione (GSH/GSSG) ratios and altered mitochondrial membrane activity in skeletal muscle, which were associated with a substantial overproduction of reactive oxygen species (ROS) in a dehydroepiandrosterone (DHEA)-induced mouse model of PCOS [134]. Furthermore, work on human adipose tissue shows that hypertrophic adipocytes maintain redox imbalance and inflammatory cytokine production by increasing free fatty acid efflux and NADPH oxidase activities.

Hyperandrogenism

One well-known characteristic of PCOS is chronic low-grade inflammation, which is a significant upstream factor in endocrine dysregulation. Disturbances in estrogen homeostasis, which represent a compromised ovarian steroid balance, are closely linked to raised inflammatory and oxidative stress-related markers in women with PCOS. It has been demonstrated that inflammatory signals promotes enhanced androgen biosynthesis in ovarian theca cells by increasing the activity of important steroidogenic enzymes.

In addition to postnatal androgen excess, emerging data suggests that exposure to androgens during fetal life may influence prolonged endocrine and metabolic susceptibility in PCOS. The second-to-fourth digit ratio (2D:4D), an indirect indicator of prenatal androgen intake, has been observed to be reduced (below 1) in women with PCOS. Additionally, a lower 2D:4D ratio has been associated with a higher incidence of depressive symptoms and a raised likelihood of insulin resistance, indicating that early androgenic programming may play a role in later onset of metabolic and neuroendocrine characteristics of PCOS [1].

Oxidative damage in PCOS is further exacerbated by androgen overload. In ovarian and peripheral tissues, increased testosterone levels promote mitochondrial respiration and ROS production that is dependent on NADPH oxidase (NOX) [128]. This results in poor oocyte maturation, p66Shc-mediated apoptosis, and mitochondrial dysfunction in granulosa cells [36, 37]. ROS buildup and cellular damage are made worse by the depletion of antioxidant defenses, especially glutathione peroxidase and catalase [133]. On the other hand, androgen surplus is encouraged by oxidative stress. ROS promote androgen production and decrease estrogen conversion by upregulating CYP17A1 (17α-hydroxylase/17,20-lyase) and downregulating CYP19A1 (aromatase) [130]. Concurrently, ROS raise levels of free testosterone in the bloodstream by inhibiting the liver's production of sex hormone-binding globulin (SHBG) [68]. By immediately promoting the generation of testosterone by theca cells via the insulin and IGF-1 signaling networks, hyperinsulinemia exacerbates this mechanism. The endocrine and metabolic instability that characterizes PCOS is reinforced by these reciprocal actions, which create a ROS androgen insulin feedback loop (Fig. 2).

Fig. 2.

Interactions among insulin resistance, hyperandrogenism, and reactive oxygen species in PCOS

Anovulation and ovarian dysfunction

Prolonged oxidative damage in the ovary interferes with ovulation and follicular growth. In granulosa cells, excessive ROS disrupt mitochondrial oxidative phosphorylation, which lowers ATP synthesis and impairs oocyte maturation [36, 37, 109]. Additionally, mitochondrial damage reduces the production of estrogen, which results in a hormonal environment that is not conducive to dominant follicle selection. Oxidative stress causes granulosa cell death and follicular atresia by altering the equilibrium between pro- and anti-apoptotic proteins at the cellular level. This is achieved by upregulating Bax and downregulating Bcl-2 [70, 71]. Additionally, PCOS ovaries exhibit abnormal angiogenesis and altered vascular endothelial growth factor (VEGF) signals, which impairs the exchange of nutrients and oxygen [27, 141]. All of these factors work together to cause follicular arrest, luteal insufficiency, and persistent anovulation: mitochondrial malfunction, poor vascularization, granulosa cell death, and faulty steroidogenesis.

Vascular dysfunction and cardiometabolic risk pathways

Oxidative damage in polycystic ovary syndrome (PCOS) has a significant impact on vascular and metabolic wellness in addition to ovarian dysfunction. According to Wang et al. [130], a surplus of reactive oxygen species (ROS) decreases the bioavailability of nitric oxide (NO) by combining with superoxide to produce peroxynitrite, a strong oxidant that harms endothelial cells and hinders vasodilation. Circulatory NO levels in PCOS-afflicted women are much less, indicating weakened endothelial cells and decreased vascular reactivity [90]. According to Daiber et al. [25], oxidative alteration of endothelial nitric oxide synthase (eNOS) causes its "uncoupling," which increases vascular oxidative strain by encouraging the generation of superoxide rather than NO. By oxidizing low-density lipoprotein (LDL), activating endothelium, and forming foam cells, prolonged oxidative damage also speeds up atherosclerotic processes, especially in insulin-resistant PCOS phenotypes.

Systemic insulin resistance and chronic low-grade inflammation are caused by ROS, which disrupt adipokine balance by lowering adiponectin and increasing pro-inflammatory cytokines including TNF-α and IL-6. These implications are compounded by adipose tissue malfunction [17, 33]. The raised cardiometabolic vulnerability in PCOS is caused by a self-perpetuating oxidative inflammatory loop with increased macrophage infiltration into adipose depots amplifying localized ROS production and cytokine secretion [67]. Furthermore, regardless of their obesity status, women with PCOS exhibit increased oxidative reactions to dietary fat intake, as evidenced by disproportionate postprandial rises in lipid peroxidation indicators. All of these events work together to connect metabolic, inflammatory, and vascular routes, emphasizing oxidative damage as a common cause of the cardiometabolic problems linked to PCOS.

Redox biomarkers in PCOS

The evaluation of oxidative load in PCOS is based on an array of biomarkers that represent several facets of redox homeostasis, such as enzymatic defense systems, antioxidant capacity, and indicators of oxidative damage. Regarding the degree of oxidative harm and its association with clinical manifestations and the advancement of disease, these biomarkers offer important information.

Markers of oxidant burden

Oxidative damage indicators that show lipid, protein, and DNA damage are consistently elevated in women with polycystic ovarian syndrome (PCOS), highlighting a systemic redox imbalance that goes beyond adiposity or insulin resistance. Malondialdehyde (MDA) is a frequently documented oxidant marker and is a crucial byproduct of lipid peroxidation. According to numerous investigations, women with PCOS have significantly greater serum or plasma MDA than healthy controls, which is indicative of severe oxidative lipid damage and compromised antioxidant capacity [29, 88]. According to a meta-analysis of 68 research covering more than 4,900 PCOS cases, oxidative lipid damage is a fundamental characteristic of PCOS. MDA concentrations were substantially greater than those of control subjects, with a standardized mean difference (SMD) of 1.9 (95% CI 1.2–2.6) [79]. Both lean and obese phenotypes exhibit these outcomes, though those with insulin resistance or lipid disorders typically have elevated levels [129].

Systemic oxidative damage is further supported by several indicators of oxidative load, including protein carbonyls, 8-hydroxy-2′-deoxyguanosine (8-OHdG), and xanthine oxidase (XO) activity. High levels of 8-OHdG in follicular fluid and serum are indicative of oxidative DNA damage, which can impair embryonic growth and oocyte competence. Furthermore, it has been found that both obese and lean PCOS women have higher levels of total oxidant status (TOS) and reactive oxygen species (ROS) generated by NADPH oxidase and mitochondria. This suggests that oxidative harm is linked to intrinsic ovarian malfunction rather than just obesity [79, 88]. Together, these results highlight the fact that elevated oxidant load in PCOS is a chronic, phenotype-independent disorder that contributes to endothelial damage, insulin resistance, and follicular atresia.

Markers of antioxidant defence

Oxidative damage is associated with a significant reduction in enzymatic and non-enzymatic antioxidant responses in women with PCOS. It is frequently noted that serum and follicular fluid contain lower levels of the core enzyme antioxidants glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD), which hinder the neutralization of hydrogen peroxide and superoxide radicals. In recent studies, these enzymes' activity is considerably reduced in PCOS patients than in controls, which indicates a disruption in redox homeostasis [124, 133]. A strong association between oxidative disequilibrium and insulin resistance is suggested by the observation of decreased total antioxidant capacity (TAC) in a number of cohorts, which frequently exhibits an inverse connection with fasting insulin and HOMA-IR (Malini et al., 2023).

Additionally, compromised in PCOS is the antioxidant defense system's non-enzymatic arm. Especially in individuals with metabolic syndrome symptoms or corpulence, concentrations of reduced glutathione (GSH), vitamin C, vitamin E, β-carotene, and retinol are often decreased. In women with PCOS, Fatima et al. [31] found significantly lower levels of GSH and vitamins C and E, which were adversely connected with insulin indices and oxidative stress indicators. According to Uçkan et al. [124], these decreases are frequently accompanied by increased levels of malondialdehyde (MDA) and total oxidant status (TOS), which indicate continued oxidative intake of antioxidants. It's fascinating to note that some research has found paradoxically high levels of SOD or GPx in early PCOS, which have been interpreted as temporary compensatory reactions to heightened reactive oxygen species. Nevertheless, as the illness progresses and antioxidant reserves are exhausted, these levels likely to decrease [133]. A persistent redox imbalance is created when reactive oxygen species generation and antioxidant depletion are consistently out of proportion. This discrepancy leads to the metabolic, vascular, and reproductive problems that are typical of PCOS (Table 1).

Table 1.

Oxidant and antioxidant biomarkers in PCOS

Biomarker	Typical biological matrix	Levels in PCOS	Significance	References
Malondialdehyde (MDA)/thiobarbituric acid reactive substances (tbars)	Serum and follicular fluid	Elevated	Indication of lipid peroxidation	[72, 74]
8-Hydroxy-2'-deoxyguanosine (8-OHdG)	Urine, follicular fluid, and granulosa cells	Elevated	Indicator of DNA damage due to oxidative stress	[82]
Protein carbonyls (PCOs)	Plasma or serum	Elevated	Marker of oxidative modification of proteins	[79]
Superoxide dismutase (SOD) activity	Erythrocytes, serum, and follicular fluid	Reduced or variable	Scavenges oxygen radicals through oxidation/reduction cycles	[117]
Catalase (CAT) activity	Serum	Reduced (mostly)	Indicates impaired peroxide detoxification	[138, 139]
Glutathione peroxidase (GPx)	Serum and follicular fluid	Reduced activity	Detoxifies the peroxides by using glutathione (GSH)	[136, 77]
Reduced glutathione (GSH)	Blood and follicular fluid	Reduced	Depletion indicates increased oxidative damage	[22, 69]
Total antioxidant capacity (TAC)	Serum/plasma	Reduced	Marker of the increased oxidative stress	[81, 107]

Mechanistic basis for antioxidant intervention

Dietary antioxidants have the ability to treat polycystic ovarian syndrome (PCOS) through complex modulation of cellular homeostasis, signaling networks, and organ-system functioning, going beyond basic free radical scavenging. Identifying the mechanisms underlying antioxidant therapy is essential for comprehending how these substances tackle the complex pathophysiology of PCOS, which includes systemic metabolic disorders and mitochondrial malfunctioning.

Rebalancing oxidative homeostasis

Antioxidants as modulators of endogenous defense systems

A basic mismatch between the generation of reactive oxygen species (ROS) and endogenous antioxidant capability is represented by the oxidative distress feature of PCOS. Direct enzyme stabilization, increased gene expression, and cofactor availability maintenance are some of the beyonisms that are extended by this dysfunction. By activating intrinsic antioxidant pathways and directly neutralizing ROS, dietary and endogenous antioxidants regulate this discrepancy. In addition to enhancing enzymatic antioxidants, vitamins C and E, coenzyme Q10, N-acetylcysteine (NAC), and selenium also restore intracellular thiol pools [58, 120]. Supplementing with NAC or CoQ10 dramatically lowers serum MDA and raises TAC and SOD function in women with PCOS, according to randomized controlled trials (RCTs) [30, 51, 52]. Additionally, intake of selenium enhances insulin sensitivity and reduces oxidative damage, supporting its function as a cofactor for GPx [140].

Preservation of mitochondrial function and cellular signaling integrity

A key factor in the pathophysiology of polycystic ovarian syndrome (PCOS) is mitochondrial malfunction, which affects apoptotic control, steroidogenesis, and cellular energy metabolism [133]. Oxidative and metabolic stress are sustained in PCOS tissues due to decreased mitochondrial DNA copy number, impaired electron transport chain function, and increased ROS production [122]. By preserving electron transport efficiency, stabilizing mitochondrial membranes, and shielding mitochondrial DNA from oxidative damage, antioxidant treatment breaks this process. MitoQ and other mitochondria-specific antioxidants have demonstrated effectiveness in DHEA-induced PCOS animal studies by restoring granulosa cell mitochondrial activity, normalizing redox regulators (TXNIP, TRX, and ASK1), and promoting folliculogenesis. They additionally attain high intra-organelle levels [97]. According to, oxidative damage also modifies cysteine residues and interferes with hormonal and metabolic signaling processes as well as redox-sensitive signaling systems. By enhancing mitochondrial efficacy and lowering mtROS, polyphenols like resveratrol and sulforaphane further stimulate mitochondrial biosynthesis via the AMPK–PGC-1α axis [115]. So, in addition to intercepting radicals, antioxidants also restore mitochondrial structure, energy equilibrium, and signaling functionality, which addresses important pathways causing metabolic and ovarian malfunction and counteracts PCOS-related oxidative damage.

Modulation of key pathways

Influence on NF-κB, AMPK, and Nrf2 Axes

Three important signaling processes—nuclear factor-κB (NF-κB), AMP-activated protein kinase (AMPK), and nuclear factor erythroid 2-related factor 2 (Nrf2)—are coordinatedly modulated by antioxidants to provide their curative advantages in PCOS. These routes are perfect candidates for therapy because they are convergent nodes where inflammation, oxidative harm, and metabolic abnormalities converge [130]. A master modulator of inflammatory reactions, the NF-κB pathway is persistently active in PCOS as a result of ongoing oxidative damage. Normally, inhibitory proteins (IκB) keep NF-κB confined in the cytoplasm. Nevertheless, IκB kinase (IKK) is activated by ROS, which causes IκB to degrade and NF-κB to move to the nucleus, starting the transcription of genes that promote inflammation [26]. NAC, resveratrol, and sulforaphane have been shown to decrease NF-κB and reduce cytokines in animal and cellular PCOS scenarios [16, 116, 119]. According to clinical research, taking 200 µg of selenium daily reduces NF-κB-mediated inflammatory genes, which lowers hs-CRP and IL-6 [58]. Systemic anti-inflammatory effects are linked to oxidative equilibrium through antioxidant-induced NF-κB suppression.

One important connection between antioxidant reactions and cellular energy condition is the AMPK system. Energy stress triggers AMPK stimulation, which suppresses anabolic activities and encourages metabolic changes that favor ATP synthesis. AMPK function is frequently decreased in PCOS, which leads to insulin resistance and metabolic abnormalities [57]. By protecting against oxidative inactivation and modifying upstream kinases, among other methods, antioxidants can maintain or improve AMPK phosphorylation. According to Jansen et al. [60], engaged AMPK then inhibits inflammatory signaling, lowers ROS generation via NADPH oxidase (Nox4), and encourages mitochondrial biogenesis. A vital controller of cellular antioxidant defense, the Nrf2 (nuclear factor erythroid 2–related factor 2) pathway induces detoxifying and cytoprotective genes to preserve the redox equilibrium. Keap1 regulates the ubiquitination and breakdown of Nrf2 under basal circumstances. This relationship is broken by oxidative or electrophilic stressors, which allows Nrf2 to nuclear translocate and attach to antioxidant response molecules (AREs). This increases antioxidant capacity by up-regulating genes like γ-glutamylcysteine ligase (GCL), heme oxygenase-1 (HO-1), and NAD(P)H quinone oxidoreductase 1 (NQO1) [80].

According to Valipour et al. (2024), inadequate Nrf2 signaling exacerbates follicular and metabolic problems in PCOS by causing increased oxidative damage, mitochondrial malfunction, and granulosa-cell death. Ovarian redox equilibrium is improved, ROS buildup is reduced, and mitochondrial capacity is restored when Nrf2 is activated (Ma et al., 20,130). Natural substances like sulforaphane and curcumin effectively stimulate Nrf2, decrease NF-κB, and stimulate AMPK, resulting in synergistic metabolic, anti-inflammatory, and antioxidant effects. Better metabolic and reproductive outcomes in women with PCOS are also associated with increased dietary consumption of Nrf2-activating phytochemicals [5, 49, 101, 110].

Downstream effects on insulin sensitivity, inflammation, and steroidogenesis

Dietary antioxidants that modulate the NF-κB, AMPK, and Nrf2 pathways produce interconnected downstream actions aimed at the endocrine, metabolic, and inflammatory abnormalities of PCOS. These regulatory systems operate together to correct ovarian steroidogenesis, reduce prolonged inflammation, and reestablish insulin sensitivity.

Systemic insulin sensitivity is improved by antioxidant-induced AMPK expression, which also increases fatty acid oxidation and glucose absorption through GLUT4 translocation while inhibiting hepatic gluconeogenesis [24]. In addition, pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β that otherwise hinder the phosphorylation of insulin receptor substrates are decreased when NF-κB signaling is inhibited. In addition to protecting pancreatic β-cells from oxidative damage, Nrf2 activation stimulates antioxidant enzymes (HO-1, NQO1), maintaining insulin receptor reactivity in specific tissues [14]. These molecular effects are supported by clinical studies showing sustained decreases in HOMA-IR, fasting insulin, and glucose after taking antioxidants in women with PCOS [40].

Pro- and anti-inflammatory activities are regulated in a reciprocal manner by antioxidant regulation of the NF-κB and Nrf2 pathways [45]. According to Saha et al. [96], Nrf2 stimulation causes the expression of cytoprotective genes like HO-1, GCLC, and NQO1 that prevent oxidative inflammatory cascades, whereas NF-κB suppression decreases the transcription of cytokines and adhesion components. This interaction reduces ovarian and systemic inflammation, which are major causes of insulin resistance and PCOS anovulation [115].

Additionally, antioxidants directly regulate ovarian steroidogenesis by means of Nrf2 and AMPK signalling. Androgen synthesis is decreased by AMPK activation, which also restricts the access of cholesterol substrates and blocks important steroidogenic enzymes (CYP17A1, HSD3B2) [48]. During oxidative damage, Nrf2-mediated antioxidant defense maintains normal follicular maturation and enzyme action, protecting the functional stability of theca and granulosa cells [36, 37]. By suppressing NF-κB-driven cytokine signaling, inflammatory factors' paracrine promotion of testosterone synthesis is also lessened. When used together, these properties improve ovulatory cyclicity and fertility results in PCOS by lowering total testosterone, DHEA-S, and the free androgen index [36, 37, 62]. The molecular rationale of antioxidant therapy in PCOS is highlighted by this coordinated modulation of the metabolic, inflammatory, and steroidogenic axis. This makes drugs that focus on NF-κB, AMPK, and Nrf2 as attractive supplementary approaches to traditional metabolic and hormonal treatments.

Systems-level outcomes

Effects on follicular health, menstrual cyclicity, and vascular function

Clinically significant enhancements in several organ systems in PCOS are a result of antioxidant therapy's molecular and pathway-level impacts. According to these systems-level results show how PCOS pathophysiology is interrelated and how antioxidants may be able to treat the syndrome's complex appearance. Since oxidative damage severely reduces granulosa cell function, follicular growth, and oocyte quality in PCOS, follicular health enhancements are a major treatment target. Oocyte competency and IVF success percentages are negatively correlated with the higher amounts of oxidative damage markers and inflammatory mediators found in the follicular fluid of women with PCOS. By addressing these anomalies at their root cause, antioxidant therapies preserve the milieu required for healthy oocyte maturation, shield granulosa cells from oxidative harm, and sustain follicular steroidogenic capability [72, 78]. Antioxidants which attack the mitochondria have been shown in experiments to recapture normal folliculogenesis in PCOS species. In DHEA-induced PCOS mice, MitoQ treatment enhanced follicular architecture, repaired estrous cyclicity, and normalized granulosa cell production of redox regulatory proteins. Likewise, afamin intake enhanced antioxidant enzyme activity in granulosa cells, decreased oxidative DNA and lipid degradation indicators, and enhanced follicular growth by protecting the mitochondria through SIRT1-dependent mechanisms [73, 138, 139]. These results offer molecular proof that enhanced reproductive function is associated with antioxidant defense.

Enhancements in menstrual cyclicity are a result of the hypothalamic-pituitary-ovarian axis functioning normally again via a variety of methods. The hypothalamic–pituitary–gonadal (HPG) axis involves highly integrated interaction between the hypothalamus, pituitary gland, and ovaries. Through this process, gonadotropin-releasing hormone (GnRH) regulate the discharge of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which in conjunction control ovarian steroid generation and regular ovulation. Whilst ovarian antioxidant defense promotes follicular growth and estradiol generation, which are essential for regular cycle progression, decreased oxidative damage in hypothalamic neurons improves GnRH pulsatility [125]. Sex steroids including estrogen, progestin, and androgens offer feedback signals within this axis, aiding to preserve hormonal balance and facilitate regular menstrual cycles. A more beneficial hormonal atmosphere for regular ovulation is also produced by decreases in hyperandrogenism and increases in insulin sensitivity. Meta-analytic proof suggests that antioxidant supplements, such as those containing N-acetylcysteine or CoQ10, could boost menstrual regularity in women with PCOS and are linked to decreases in total testosterone and diagnostic hyperandrogenism levels [9, 46, 137, 142]. By improving vascular activity, PCOS-related heightened cardiovascular risk is mitigated in a number of ways. Prolonged oxidative strain, inflammation, and metabolic irregularities that enhance atherosclerotic events and reduce nitric oxide bioavailability cause endothelial impairment in PCOS. Antioxidant therapies minimize inflammatory factors that fuel vascular dysfunction, protect endothelial cells from oxidative damage, and maintain nitric oxide synthase functioning. According to clinical research, using antioxidant supplements results in slight but steady changes in lipid profiles, blood pressure, and endothelial function indicators. The potential of antioxidants to target several pathophysiologic pathways at once is reflected in the systems-level advantages of antioxidant intervention in PCOS. Antioxidants provide a mechanistically sound method of managing PCOS that enhances current treatment approaches by reestablishing oxidative balance, modifying important signaling pathways, and safeguarding cellular function throughout organ systems. Future studies should concentrate on creating biomarkers to direct tailored therapies and enhancing antioxidant selection, dosage, and harmony techniques to optimize these systems-level advantages. (Table 2).

Table 2.

Antioxidant-driven treatments and their impact in experimental animal models of PCOS

Antioxidant	Experimental model	Dose	Key effects	Reference
N-acetylcysteine (NAC)	Letrozole-induced PCOS mouse model	160 mg/kg/day (Orally)	Enhanced endocrine, metabolic, oxidative stress, and ovulation factors in PCOS	[30]
Resveratrol	Testosterone-induced PCOS rat model	10 mg/kg/day (Intraperitoneal)	Decreased oxidative load and insulin resistance in PCOS	[41]
Alpha-Lipoic Acid (ALA)	Letrozole-induced PCOS rat model	1 mg/day (Orally)	Decreased inflammation, metabolic abnormalities, and hormonal imbalance in PCOS	[32]
Astaxanthin (ASX)	Letrozole-induced PCOS rat model	40 mg/kg/day (Orally)	Decreased ovarian oxidative damage, inflammation, and cellular harm in PCOS	Erdem [123]
Vitamin E (α-tocopherol)	DHEA-induced PCOS rat model	200 mg/kg/day (Orally)	Reduced hyperandrogenism, oxidative load, and ovarian apoptosis in PCOS	[83]

Dietary antioxidants in PCOS

Antioxidant nutrients

Vitamin E

In the treatment of polycystic ovarian syndrome (PCOS), the curative properties of antioxidant vitamins in particular, vitamin C (ascorbic acid) and vitamin E (α-tocopherol) have drawn greater interest. These nutrients work together as complementing antioxidants: vitamin E maintains lipid membranes by halting peroxidation, while vitamin C eliminates reactive oxygen species in aqueous conditions. Repairing redox equilibrium by dietary antioxidants may help address numerous important disruptions in PCOS, as oxidative overload is a contributing factor to insulin resistance, dyslipidemia, and disrupted folliculogenesis [137]. Vitamin E has demonstrated the most persistent beneficial effects among the antioxidant vitamins that have been investigated. Vitamin E supplementation, either by itself or in combination with omega-3 fatty acids or magnesium, substantially decreased triglycerides, total cholesterol, LDL cholesterol, and high-sensitivity C-reactive protein (hs-CRP), while boosting nitric-oxide bioavailability, an indicator of better endothelial health, according to a recently published meta-analysis of randomized controlled trials [47]. Concurrent improvements in total testosterone, sex-hormone-binding globulin (SHBG), insulin resistance (HOMA-IR), and fasting glucose were verified by another pooled analysis, indicating that vitamin E affects both hormonal and metabolic control in PCOS [132]. Vitamin E has potential benefits for ovarian vascular health in addition to its metabolic benefits. In a controlled study, taking 400 IU of vitamin E daily for eight weeks resulted in a substantial decrease in vascular endothelial growth factor (VEGF) and a return to normal of the angiopoietin-1/angiopoietin-2 ratio. These improvements are associated with enhanced follicular maturation and better ovarian angiogenesis [106]. Likewise, the combination of magnesium and vitamin E improved lipid metabolism and glycemic management, suggesting that antioxidants and minerals work in concert [15, 108].

Vitamin C

Although there is less data, vitamin C's role in PCOS is nonetheless biologically encouraging. In the ovary, ascorbic acid promotes the activity of steroidogenic enzymes and replenishes oxidized vitamin E. Vitamin C treatment repaired oxidative-stress indices including glutathione and superoxide dismutase, decreased the production of cystic follicles, and enhanced ovarian shape in an experimental PCOS model [84]. Nutritional strategies have shown that appropriate vitamin C administration improves overall antioxidant capacity and assists in repairing plasma deficits in women with PCOS, despite the paucity of human evidence on the subject [87]. While recognizing the lack of well-designed vitamin C-specific trials, broader evaluations of the nutraceutical strategy also highlight vitamins C and E as important agents for reducing oxidative damage and hormonal fluctuations [126, 137] (Table 3) (Fig. 3).

Table 3.

An overview of clinical research assessing antioxidant-based treatments for PCOS-afflicted women

Antioxidant	Study design	Population	Dosage	Duration	Endpoints	References
N-acetylcysteine (NAC) + clomiphene citrate (CC)	Placebo-controlled double-blind randomized clinical trial	180 PCOS infertile patients	1200 mg/d	3 months	Increased follicular development and pregnancy results	[98]
N-acetylcysteine (NAC) + clomiphene citrate (CC)	Randomized controlled trial	150 infertile women with PCOS	1200 mg/d	12 weeks	Higher rates of ovulation and pregnancy	[44]
N-acetylcysteine	Prospective comparative study	100 patients of PCOS	1800 mg/d	24 weeks	Better hormonal and metabolic profiles	[18]
Resveratrol	Double-blind, Randomized, Placebo-controlled Trial	30 women with PCOS	1,500 mg/d	3 months	Enhanced insulin sensitivity and decreased androgen levels	[12]
Resveratrol	Triple-blind RCT	61 PCOS patients	800 mg/d	40 days	Better embryo quality and hormonal equilibrium
Coenzyme Q10 (CoQ10)	Randomized, double-blinded, parallel, placebo-controlled	40 PCOS-positive infertile women	100 mg/d	8 weeks	Enhanced metabolic profiles and insulin sensitivity	[3]
CoQ10 + Vitamin E	Randomized, double-blind, placebo-controlled trial	86 women with PCOS	200 mg/d	8 weeks	Better cardiometabolic and lipid levels	[51, 52]
CoQ10 + Vitamin E	Randomized, double-blind, placebo-controlled clinical trial	86 women with PCOS	200 mg/d	8 weeks	Enhanced androgen and insulin profiles	[51, 52]
Astaxanthin (ASX)	Randomized clinical trial	58 PCOS patients	12 mg/d	60 days	Lowered ER stress and greater oocyte quality	[54]
Astaxanthin (ASX)	Randomized, double-blind clinical trial	56 PCOS patients	12 mg/d	8 weeks	Reduced inflammation and ER stress	[53, 55, 56]
Astaxanthin (ASX)	Randomized clinical trial	58 PCOS patients	12 mg/d	8 weeks	Regulated apoptosis and increased anti-apoptotic expression	[53, 55, 56]
Alpha-lipoic acid (ALA)	Randomized, single-blind clinical trial study	90 PCOS patients	600 mg/d	12 weeks	Better ovarian and hormonal implications
Alpha-lipoic acid (ALA) + myoinositol (MYO)	Retrospective case–control study	58 PCOS patients	400 mg/d	24 months	Maintained weight and enhanced glycemic management	[34]
Alpha-lipoic acid (ALA) + myoinositol (MYO)	Retrospective observational study	88 PCOS patients	800 mg/d	6 months	Enhanced menstrual cyclicity and metabolic profile	[35]
Vitamin E	Retrospective cohort clinical trial	320 PCOS patients	100 mg/d	12 weeks	Improved oxidative stress, and decreased exogenous human menopausal gonadotropin (HMG) intake	[21]
Vitamin E	Randomized, double-blind, placebo-controlled trial	43 PCOS patients	400 IU/d	8 weeks	Lowered body weight and angiogenic indicators	[106]
Magnesium and vitamin E	Randomized, double-blind, placebo-controlled trial	60 women with PCOS	400 mg/d	12 weeks	Better lipid composition and insulin sensitivity	[59]

Fig. 3.

Vitamins E and C driven restoration of ovarian and metabolic outcomes

N-Acetylcysteine

The thiol-rich precursor of glutathione, N-acetylcysteine (NAC), has drawn a lot of interest as a metabolic and reproductive aid in PCOS. NAC reduces oxidative stress-induced deficits in insulin receptor functioning and ovarian physiology by serving as a direct antioxidant and an insulin signaling regulator. For women with PCOS, especially those receiving ovulation-induction (OI) medication, these two actions make NAC an appealing therapeutic alternative [70, 71, 85, 120]. NAC intake has been shown in numerous clinical and translational studies to boost ovulatory results and increase insulin sensitivity. In comparison to control subjects who received a placebo or metformin, a multicenter randomized controlled trial (RCT) of women with PCOS found that NAC in conjunction with standard letrozole or urinary FSH treatment substantially boosted ovulation and clinical pregnancies [30]. According to Viña et al. [127], these results add to preclinical data that NAC reinstates ovarian steroidogenesis and reverses insulin receptor sensitivity in hyperandrogenic experimental animals.

Previous clinical studies demonstrated that NAC has an insulin-sensitizing effect. NAC intake dramatically reduced fasting insulin, HOMA-IR, and triglyceride concentrations in a head-to-head juxtaposition to metformin, showing similar metabolic effectiveness with better tolerability [7]. Another investigation that combined NAC with folic acid and myo-inositol for a year revealed changes in ovulation occurrence and monthly regularity as well as significant decreases in HOMA-IR [95]. These conclusions were supported by two recent meta-analyses. Supplementing with N-acetylcysteine (NAC) dramatically lowers total testosterone and raises FSH concentrations in PCOS-afflicted women, suggesting better reproductive hormonal equilibrium [103]. A more thorough meta-analysis by Viña et al. [127] revealed that NAC significantly impacted the amounts of LH, progesterone, and endometrial thickness in PCOS-afflicted women. NAC is a secure, economical, and mechanistically sound adjuvant for PCOS, especially in phenotypes that are insulin-resistant and clomiphene-resistant, according to the available data. Its dual redox and insulin-sensitizing properties offer benefits that could supplement pharmacologic OI regimens and possibly lower the dosages of medications needed.

Alpha-lipoic acid

Alpha-lipoic acid (ALA) is a dithiol molecule that occurs naturally and has strong antioxidant and mitochondrial cofactor qualities. In polycystic ovarian syndrome (PCOS), it has garnered a lot of attention as a metabolic regulator. By restoring mitochondrial redox equilibrium and improving glucose absorption through GLUT-4 translocation, ALA helps impacted women's metabolism and reproductive processes [102]. ALA significantly enhances lipid metabolism and insulin sensitivity in a variety of PCOS phenotypes, according to clinical trials. A beneficial shift toward bigger and more buoyant LDL subclasses was observed in lean women who received controlled-release ALA (600 mg twice daily for 16 weeks). These results suggest enhanced insulin action and lipid remodeling. Additionally, ALA enhanced insulin sensitivity by 13.5% and decreased triglycerides [75]. According to Genazzani et al. [39], low-dose ALA substantially lowered fasting insulin, glucose, BMI, and HOMA-IR in obese PCOS patients. The benefits were particularly noticeable in individuals with a family history of diabetes.

ALA seems to have additional or even synergistic benefits when mixed with inositols. Over seventy percent of those enrolled in a six-month study using ALA plus myo-inositol experienced an improvement in menstrual regularity, and insulin-resistant women demonstrated significant decreases in fasting insulin and HOMA-IR. The most significant reproductive outcomes were generated by the higher inositol dose, indicating a dual mechanism that is both insulin-dependent and insulin-independent [35]. These findings were further supported by a thorough synthesis by Guarano et al. [43], which highlighted the anti-inflammatory, antioxidant, and insulin-sensitizing properties of ALA, especially in obese females with PCOS or those with type 2 diabetes. Emerging clinical data also shows temporary metabolic advantages: three months of paired ALA and myo-inositol decreased LDL cholesterol, increased glycemic indicators, and maintained body weight and BMI as in comparison with untreated subjects [34]. When combined, these results demonstrate that ALA is a versatile treatment that tackles insulin resistance, dyslipidemia, and oxidative damage concurrently. ALA is a viable integrative approach for enhancing metabolic regulation and reestablishing reproductive cyclicity in women with PCOS, either by itself or in conjunction with inositols.

Coenzyme Q10 and resveratrol

Women with polycystic ovarian syndrome (PCOS) have metabolic and vascular abnormalities that make supplementary antioxidant and mitochondrial modulating treatments a viable option. The antioxidant, mitochondrial, and hormone-regulating qualities of coenzyme Q10 (CoQ10) and resveratrol have drawn interest among new adjunctive therapies. These medications target common biological processes linked to the pathophysiology of PCOS, such as mitochondrial signals, oxidative damage, and inflammatory processes.

CoQ10 has been studied in women with PCOS in a number of controlled, randomized studies. Ahmadi Asouri et al. [3] discovered that CoQ10 administration raised PPAR-γ expression and decreased insulin and HOMA-IR in infertile PCOS women undergoing IVF. Taghizadeh et al. [114] shown that CoQ10 improved inflammatory markers and functioning of endothelial cells in overweight PCOS patients by lowering TNF-α, IL-6, hs-CRP, VCAM-1, and E-selectin. CoQ10, either by itself or in combination with vitamin E, enhanced fasting glucose, insulin, HOMA-IR, and testosterone, whereas co-supplementation increased SHBG, according to Izadi et al. [51, 52]. Furthermore, Zhang et al.'s meta-analysis from 2022 verified that CoQ10 improves lipid profiles, insulin resistance, and hormone equilibrium without having any unfavorable outcomes.

Resveratrol has shown supplementary vascular and endocrine advantages. Resveratrol decreased total testosterone by 23%, DHEAS by 22%, fasting insulin by 31.8%, and enhanced insulin sensitivity by 66% when contrasted with a control group in a seminal double-blind RCT [12]. Resveratrol intake substantially lowered testosterone, luteinizing hormone (LH), and dehydroepiandrosterone sulfate (DHEAS), according to a recently published meta-analysis of randomized trials involving 218 women. This finding supports the effectiveness of resveratrol in reducing hyperandrogenism in PCOS [6]. In support of these results, Dubey et al. [28] concluded that resveratrol enhances metabolic indices, oxidative stress indicators, and ovarian morphology, demonstrating its wide-ranging regulatory impact on the hormonal–metabolic relationship. Resveratrol decreased the expression of the VEGF and HIF-1 genes in granulosa cells and enhanced the quality of oocytes and embryos, according to an RCT by Bahramrezaie et al. [11]. This suggests that ovarian angiogenesis and follicular maturation are beneficially modulated. Resveratrol restores follicular growth in PCOS mice by reducing ovarian inflammation and NLRP3/GSDMD/Caspase-1-mediated pyroptosis, while women also experience clinical enhancements in menstrual regularity, according to research conducted by Wei et al. [131]. Mechanistic syntheses by Chang et al. [19] additionally suggests SIRT1 stimulation, anti-inflammatory signals, and mitochondrial control as essential mechanisms driving resveratrol’s metabolic and endocrine effects. All of these results point to resveratrol as a bioactive polyphenol with a variety of medicinal uses in the treatment of PCOS.

Astaxanthin

A marine-based xanthophyll carotenoid, astaxanthin (ASX) is well known for its remarkable antioxidant and mitochondrial defense properties. Its distinct molecular structure, in contrast to other carotenoids, allows for the effective quenching of singlet oxygen and the stability of cellular membranes against oxidative damage. When it comes to polycystic ovarian syndrome (PCOS), astaxanthin has shown promise as a dietary antioxidant that can alter important metabolic and reproductive processes. Astaxanthin regulates the endoplasmic reticulum (ER) and oxidative damage reactions in ovarian tissue, according to mechanistic and translational research. Women with PCOS showed noteworthy decreases in the ER-stress indicators GRP78 and CHOP as well as a major rise in total antioxidant capacity (TAC) in follicular fluid during a 60-day randomized controlled trial, this suggests that granulosa cells have better proteostatic balance [54]. Additional data from a triple-blind RCT revealed notable reductions in fasting glucose, HOMA-IR, LDL cholesterol, and malondialdehyde (MDA), along with simultaneous boosts in HDL-C and TAC. These findings conjointly suggested improved redox and metabolic equilibrium [53, 55, 56]. These results are corroborated by experimental data from letrozole-induced PCOS models, which show that ASX treatment suppresses ovarian NF-κB, TNF-α, and IL-6 production and restores follicular morphology [118, 123]. In conclusion, astaxanthin is a biologically tenable and growingly supported antioxidant option for the treatment of PCOS. Its proven ability to improve insulin action, reduce ER stress, and repair redox homeostasis makes it a useful supplement to antioxidant-centered treatment plans (Fig. 4).

Fig. 4.

Overview of the mechanisms underlying astaxanthin's therapeutic properties

Dietary patterns and whole-food approaches

Antioxidant-rich dietary models and systemic effects

The need to shift from single-nutrient supplements to broad, antioxidant-rich eating habits that boost endogenous defense mechanisms and alter metabolic pathways in order to address oxidative stress in PCOS is becoming increasingly apparent. The Mediterranean diet, or MedDiet, has drawn the most curiosity among these. The MedDiet provides a synergistic network of antioxidant and anti-inflammatory chemicals and is marked by a moderate consumption of fish and a restricted ingestion of processed foods, along with an abundance of fruits, vegetables, legumes, whole grains, nuts, and extra virgin olive oil [13]. Its abundance of polyphenols, carotenoids, vitamins C and E, and unsaturated fatty acids may be able to influence the pathophysiology of PCOS by modifying inflammatory responses, oxidative stress, and hormonal signaling [4]. Prior research has repeatedly shown that better metabolic and oxidative patterns in PCOS are associated with greater adherence to the MedDiet. According to Barrea et al. [13], women with PCOS consumed fewer anti-inflammatory foods, adhered less closely to the Mediterranean diet, and had greater levels of insulin resistance, inflammatory markers, and testosterone. After controlling for lifestyle and anthropometric factors, Ajorlouie et al. [4] found that higher Prime Diet Quality Score and more compliance to the Mediterranean diet were linked to considerably decreased risks of PCOS, underscoring the preventive impact of diet quality. Kurtbeyoğlu et al. (2021) found that women with PCOS had poor adherence to the Mediterranean diet, which was inversely connected with progesterone concentrations.

Çıtar Dazıroğlu & Acar Tek [23] highlighted that one of the characteristics of PCOS is persistent, low-grade inflammation. They suggested that the components of the Mediterranean diet, specifically omega-3 fatty acids, antioxidants, and dietary fiber, may reduce this kind of inflammation in a number of ways. In their evaluation of the data relating to the Mediterranean diet and reproductive health consequences, Szmidt et al. [113] came to the conclusion that, although the outcomes of various research studies were not completely congruent, more adherence was generally linked to positive trends in PCOS. By enhancing dietary compliance, nutrition understanding, and behavioral involvement, Scannell et al. [99] showed that a 12-week ad libitum Mediterranean diet therapy was both practical and suitable for women with PCOS. All of these investigations show that following the Mediterranean diet is linked to better hormonal, inflammatory, and metabolic characteristics in PCOS and may help avert and cure the condition.

When combined, these results emphasize how crucial it is to take the entire dietary context into account when analyzing the clinical outcomes of specific antioxidant treatments in PCOS. It is essential to recognize that the overall dietary habits of the subjects in clinical and experimental studies may have some bearing on the positive effects linked to dietary antioxidant supplementation in women with PCOS. Antioxidant compounds, polyphenols, vitamins, and unsaturated fatty acids are naturally abundant in dietary models like the Mediterranean-style diet, plant-based diets, and Nordic dietary patterns. These components have been individually demonstrated to enhance insulin sensitivity, lower systemic inflammation, and regulate oxidative stress in PCOS. Hence, the reported metabolic and reproductive beneficial effects of antioxidant supplementation should be examined within the larger context of background diet quality, which may serve as a synergistic or confounding variable.

Furthermore, other nutraceuticals and functional foods have been suggested as an efficient approach to the management and prevention of noncommunicable diseases, including PCOS, when paired with healthy eating habits like the Mediterranean diet and consistent exercise. This integrated lifestyle method has been linked with improvements in oxidative load, insulin resistance, and inflammatory condition, which are important pathophysiological characteristics shared by PCOS and other noncommunicable disorders.

According to recent research, certain nutraceuticals, especially flavonoids and inositols, improve insulin sensitivity and reduce oxidative stress in PCOS patients [112]. Furthermore, it has been established that oxidative strain, essential trace elements, and potentially toxic elements (PTEs) are associated in women with PCOS, suggesting that environmental exposure and micronutrient imbalances may play a role in redox dysregulation. When considered collectively, these results imply that nutraceutical interventions might be most successful when paired with good agricultural practices and healthy eating habits that guarantee sufficient intake of essential elements while reducing exposure to PTEs, promoting a pragmatic, food-system-oriented strategy for PCOS management [66, 89]. Recent research indicates a strong correlation between gut microbiota composition and the impact of functional foods, nutraceuticals, and dietary practices on PCOS. Changes in the diversity and functionality of gut microbes have been associated with oxidative load, inflammation, and metabolic dysregulation in PCOS, suggesting that the gut microbiota may mediate impacts associated with nutrition and nutraceuticals [42, 76].

Limitations and future directions

Contemporary knowledge and clinical utilization of antioxidant treatment in PCOS are limited by a number of important limitations, despite the strong molecular explanation and growing clinical data. The majority of controlled studies that have examined antioxidants in PCOS have had limited sample numbers, which restricts the result's statistical power and generalization [79, 127]. Furthermore, the majority of therapies have only been studied for 8–24 weeks, which is too short a time frame to evaluate the longevity, safety, and durability of benefits [70, 71, 142]. Systematic evaluation and meta-analysis are difficult due to the diversity in study populations, therapeutic protocols, dosage schedules, and outcome metrics among trials, which hinders the creation of medical guidelines [142].

Furthermore, there is still a dearth of long-term safety information regarding antioxidant supplementation in PCOS. Long-term or high-dose antioxidant consumption may possibly interfere with physiological redox signaling, which is necessary for normal metabolic regulation and ovulatory function, even though the majority of treatment trials indicate good short-term tolerability. There is not enough research done on compound-specific factors, such as possible interactions with hormonal treatments, insulin-sensitizing medications, or underlying thyroid and metabolic conditions. Furthermore, there is a shortage of information on longer reproductive follow-up, fertility treatment settings, and safety during pregnancy [69].

Another possible cause of bias that needs to be carefully taken into account is lifestyle-related factors that have a direct impact on oxidative and metabolic outcomes. The effect of physical activity, which is believed to individually modulate insulin sensitivity, inflammatory signaling, mitochondrial function, and oxidative damage in women with PCOS, is another restriction that needs to be carefully considered. Frequent exercise treatments have been demonstrated to enhance metabolic and reproductive outcomes in PCOS, which may complicate the interpretation of impacts related to antioxidants in both experimental and clinical research. Nevertheless, physical activity levels are often poorly assessed, inconsistently reported, or not taken into account in studies assessing antioxidant supplementation. The molecular knowledge regarding how antioxidant therapies convert biochemical enhancements into clinically significant results is severely lacking. Although numerous studies show changes in oxidative damage indicators such malondialdehyde and total antioxidant capacity, it is still unclear how these modifications relate to metabolic or reproductive consequences. Additionally, the majority of clinical trials have concentrated on systemic indicators of oxidative strain rather than tissue-specific impacts on insulin-sensitive tissues or ovarian follicles, where therapeutic advantages would be most pertinent [72, 78]. One major methodological barrier impeding advancement in the field is the absence of validated outcomes and standardized biomarker panels for oxidative strain evaluation in PCOS [79].

To increase the therapeutic value of antioxidant treatment in PCOS, future studies should focus on a few important areas. There is an urgent need for large-scale, multicenter randomized controlled studies with sufficient power to identify clinically significant variations in key outcomes like insulin sensitivity, ovulation rates, and pregnancies. To improve comparability and make meta-analyses easier, these trials should use standardized procedures for participant recruitment, intervention administration, and outcome evaluation [46]. Mechanistic research that combines multi-omics techniques, ovarian tissue biomarkers, and follicular fluid testing may clarify the mechanisms by which antioxidants work and find prognostic markers for therapy responsiveness.

One prospective path toward improving the effectiveness of antioxidants for PCOS is the advancement of precision medicine techniques. Because the condition is heterogeneous, certain antioxidant therapies may have a preferential effect on particular manifestations. To find the best treatment algorithms, future research should group individuals according to metabolic and reproductive characteristics, genetic polymorphisms influencing antioxidant metabolism, and baseline damage state [8, 142]. Furthermore, studies on combination treatments, customized dosage plans, and improved delivery systems may be able to optimize therapeutic results while reducing side effects. To determine how long treatment benefits last and evaluate any possible hazards related to extended-term antioxidant administration, ongoing monitoring studies are crucial.

Conclusion

Oxidative stress has emerged as a major focus for better understanding and treating PCOS, according to mounting data. Hormonal and metabolic health may be supported by dietary antioxidants that aid in cellular equilibrium restoration. Even though a lot of research shows promising findings, it is challenging to draw definitive conclusions due to variations in sample size and study design. Standardized markers and more thorough trials should be the main focus of future research to determine their actual clinical relevance. Antioxidant-based diets customized to each person's unique profile may improve PCOS management and convert scientific discoveries into long-lasting, practical advantages for women's health.

Authors’ contributions

Nevin Adel Amer1,2, Shatha Basheer Aldababseh3,4, Doha Abdel Hady Abdel Gawad5,6, Mostafa M Abdelsadek7, Rania Abdel Khalik Gouda8,9, Abdela Befa Kinki-all the authors have take part equally.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

The datasets generated used and/or analyzed during the current study available from the corresponding author on reasonable request.

Declarations

Ethics and approval and consent to participate

Not applicable.

All the co-authors are willing to participate in this manuscript.

Consent for publication

All authors are willing for publication of this manuscript.

Competing interests

The authors declare no competing interests.