Search Results (254)

Previously, the role of decreased biodiversity of gut microbiota in polycystic ovary syndrome (PCOS) was demonstrated, but the objective criteria for assessing the representation of microorganisms associated with hyperandrogenemia (HA) were limited. A total of 175 premenopausal women (26 women with PCOS and HA and 149 women without HA, including 19 healthy controls) were recruited during the Eastern Siberia PCOS Epidemiology and Phenotype (ESPEP) Study (2016–2019). Methods included a questionnaire survey, clinical examination, pelvic U/S, blood and feces sampling. Gut microbiome was analyzed by high-throughput sequencing of the V1–V3 of the variable regions of the 16S rRNA gene (Illumina MiSeq, San Diego, CA, USA). Amplicon libraries of 16S rDNA were processed using the QIIME2 bioinformatics pipeline. All data were analyzed using R 3.6.3. The gut microbiocenosis in women with HA was characterized by a higher representation of Lactobacillus and a lower prevalence of the Clostridia class. For Faecalibacterium, Christensenellaceae_R-7_group, and [Eubacterium] eligens group the cut-off values of their relative presence, associated with HA, were estimated as: ≤0.043%, ≤0.039%, and ≤0.02%, respectively. Conclusions: Women with PCOS-associated HA demonstrate a lower prevalence, predominantly, of Clostridia class gut microorganisms, compared with those without any forms of HA. The study presents the quantitative criteria for assessing the representation of gut microorganisms, negatively associated with hyperandrogenic phenotypes of PCOS. The threshold values proposed may be useful to justify the administration of probiotics in PCOS patients with HA. Full article

Polycystic Ovary Syndrome (PCOS) is characterized by a self-perpetuating vicious cycle between insulin resistance (IR) and hyperandrogenism (HA). While lifestyle management remains the internationally recommended first-line treatment, current clinical management, primarily relying on combined oral contraceptives and metformin, offers symptomatic relief or “masking” of the phenotype but fails to adequately disrupt this core pathophysiological loop, while also carrying potential intergenerational safety concerns. This review systematically evaluates the paradigm shift toward mechanism-based precision medicine. First, we analyze emerging precision-targeted therapies that intervene in specific pathological nodes: (1) metabolic regulators (e.g., GLP-1RAs, SGLT2i, and brown adipose tissue (BAT) activators) that target systemic glucotoxicity and the novel “BAT-Ovarian axis”; (2) neuroendocrine modulators (e.g., NK3R antagonists) that act as negative modulators of the hyperactive GnRH pulse generator; and (3) innovative androgen synthesis inhibitors (e.g., Artemisinins) that utilize a degradation-at-source mechanism. Complementing these, we explore the strategic value of Natural Products through the lens of “Network Pharmacology”, highlighting their ability to restore systemic homeostasis via multi-target modulation. Finally, we address critical translational challenges, specifically the need to establish long-term reproductive and offspring safety, providing a roadmap for developing true disease-modifying treatments for PCOS. Distinct from reviews limited to isolated therapeutic modalities, this article uniquely bridges current clinical management with emerging organ-specific precision targets and natural product networks. Full article

Objectives: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder with diverse pathogenetic mechanisms and clinical manifestations. Phenotype D PCOS is characterized by oligomenorrhoea and polycystic ovaries without hyperandrogenism. Altered adipokine profiles may contribute to reproductive and metabolic disturbances. Chemerin is an adipokine involved in inflammatory and metabolic processes. It remains unclear whether altered chemerin levels in PCOS reflect metabolic dysfunction alone or are directly associated with hyperandrogenism. The aim of this study was to compare serum chemerin levels in women with normoandrogenic PCOS and a control group. Methods: This cross-sectional preliminary study included 49 women with phenotype D PCOS and 40 healthy, age- and body mass index (BMI)-matched controls. Anthropometric, biochemical, hormonal parameters, and serum chemerin concentrations were assessed. Results: Serum chemerin concentrations did not differ significantly between the groups. In the PCOS group, the 95% confidence interval ranged from 198.61 to 234.37, while in the controls, it ranged from 187.13 to 216.21. In women with PCOS, chemerin showed significant positive correlations with weight, BMI, waist and hip circumference, total adipose tissue, and both gynoid and android fat content. Positive correlations were also observed with highly sensitive C-reactive protein (hs-CRP), insulin, glucose, triglycerides, and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and a negative correlation was found with high-density lipoprotein (HDL) cholesterol. Chemerin was weakly negatively correlated with sex hormone binding globulin (SHBG) and positively correlated with the free androgen index (FAI). In the control group, chemerin correlated positively with CRP, insulin, triglycerides, total and gynoid adipose tissue, and negatively correlated with HDL cholesterol and SHBG. Conclusions Although chemerin levels did not differ from controls, chemerin was associated with metabolic and inflammatory markers in both groups. These findings should be considered preliminary due to the limited sample size. Chemerin may reflect metabolic and inflammatory status rather than hyperandrogenism in normoandrogenic PCOS. Full article

Selective inhibition of CYP17A1 17,20-lyase is critical for treating hyperandrogenic disorders without the cortisol-depleting side effects of non-selective drugs like abiraterone. We evaluated tanshinones from Salvia miltiorrhiza as potential selective inhibitors using biochemical assays and computational modeling. Dihydrotanshinone (DT) emerged as the superior candidate; at 10 µM, it inhibited 17,20-lyase activity by 56.6% while preserving >93% of 17α-hydroxylase activity. This yields a selectivity index of 8.67, drastically outperforming abiraterone (0.73). Furthermore, DT displayed minimal off-target inhibition of CYP21A2 (14.9%) compared to abiraterone (29.8%). Molecular modeling suggests DT’s efficacy arises from a unique, functionally disruptive binding pose rather than superior thermodynamic affinity. Consequently, DT is validated as a potent natural product lead. Its dual selectivity over 17α-hydroxylase and CYP21A2 establishes the tanshinone scaffold as a promising candidate for developing safer therapies that suppress androgens while sparing cortisol biosynthesis. Full article

Background: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder characterized by hyperandrogenism, ovulatory dysfunction, and an increased prevalence of metabolic syndrome. Clusterin (CLU), a chaperone protein induced by cellular stress and known to play roles in inflammation, oxidative stress, and lipid metabolism, may be associated with the metabolic abnormalities observed in patients with PCOS. The purpose of this current study is to investigate serum CLU levels and their link with endocrine, biochemical, and metabolic parameters, such as metabolic syndrome, among women with PCOS. Methods: This cross-sectional study included 40 women aged 18–30 with PCOS diagnosed according to the Rotterdam criteria and 40 age- and BMI-matched healthy controls. Demographic data, Ferriman–Gallwey scores, hormonal and metabolic parameters (including TSH, prolactin, 17-OH progesterone, total testosterone, insulin, AMH, HOMA-IR, and serum CLU levels), and ultrasonographic ovarian morphology were assessed. Statistical analyses, including ROC and logistic regression, were performed. Results: Women with PCOS had higher follicle counts, Ferriman–Gallwey scores, LH/FSH ratios, fasting insulin levels, HOMA-IR, triglycerides, and systolic blood pressure than controls, whereas menstrual cycle frequency and HDL levels were lower (all p < 0.05). Serum CLU concentrations were markedly higher in the PCOS cohort. In the PCOS population, CLU showed positive relationships with the Ferriman–Gallwey score, fasting glucose, fasting insulin, HOMA-IR, and triglycerides, and a negative correlation with HDL. CLU levels were significantly higher in women with metabolic syndrome in the PCOS cohort compared to those without. In logistic regression analysis, CLU, AMH, and the LH/FSH ratio emerged as independent predictors of PCOS. Furthermore, CLU remained an independent predictor of metabolic syndrome in the PCOS cohort. In ROC analysis, CLU demonstrated strong diagnostic efficacy in detecting both PCOS (AUC = 0.834) and metabolic syndrome in patients with PCOS (AUC = 0.804). Conclusions: Our results show that serum CLU is higher in women with PCOS and is associated with the clinical and metabolic features peculiar to patients with PCOS. CLU was found to distinguish between patients with PCOS and healthy women and demonstrated a strong association with the presence of metabolic syndrome within the PCOS group. Overall, these findings suggest that CLU may be a valuable auxiliary biomarker for detecting women with PCOS at risk for metabolic disturbances. Full article

The study of ovarian biology is hampered by the lack of in vitro models that faithfully recapitulate the physiology of granulosa cells (GCs). Primary GCs have a limited lifespan, while most immortalized lines are tumor-derived and exhibit non-physiological hormonal responses. The purpose of this study was to develop and characterize a novel immortalized GC line with a stable, physiologically relevant phenotype. We immortalized primary murine GCs from early antral follicles using lentiviral vector to introduce human telomerase reverse transcriptase (hTERT) gene to create the IMG-A1 cell line. The line was extensively characterized using molecular (qRT-PCR, Western blot), cytogenetic (karyotyping), and functional (hormone stimulation, ELISA, proliferation assays) methods to assess its phenotype and responsiveness to gonadotropins and metabolic stressors. Exhibiting a non-transformed phenotype, IMG-A1 cells retain a stable karyotype and express the follicle-stimulating hormone receptor (FSHR) but not the luteinizing hormone/chorionic gonadotropin receptor (LHCGR). Accordingly, they respond to FSH by upregulating steroidogenic genes like aromatase (Cyp19a1) but are unresponsive to LH/hCG. Furthermore, the line exhibits physiologically relevant responses to hormonal stimulation, including a strong induction of aromatase by FSH and its synergistic upregulation in a hyperandrogenic and hyperinsulinemic milieu. The IMG-A1 cell line is a unique and robust model of early antral granulosa cells, offering a valuable new tool for studying FSH-dependent folliculogenesis, cellular aspects of ovarian pathophysiology, and drug discovery. Full article

Background: The study aimed to evaluate the efficacy of a combination of Dioscorea villosa (containing diosgenin), vitamin D, and α-lactalbumin, in women with Polycystic Ovary Syndrome (PCOS) phenotype D. The primary objective was to investigate improvements in menstrual cycle regularity. Methods: A total of 24 women aged 22–34 years with PCOS phenotype D received daily supplementation with 600 mg Dioscorea villosa (120 mg diosgenin), 100 mg α-lactalbumin, and 50 μg vitamin D for six months. Clinical and biochemical assessments, including hormonal profiling and menstrual cycle monitoring, were conducted at baseline (T0), after 3 months (T1), and after 6 months (T2). Results: The treatment led to a statistically significant improvement in menstrual cycle regularity: eumenorrhea was achieved in 50% of patients at T2, compared to 0% at baseline. Significant changes were also observed in luteinizing hormone (LH), follicle-stimulating hormone (FSH), and the LH/FSH ratio, alongside a reduction in insulin and HOMA-index at T1. No adverse events were reported. Conclusions: The combination of Dioscorea villosa, vitamin D, and α-lactalbumin promotes menstrual cycle regularization in women with PCOS phenotype D. The positive result suggests a beneficial role of the treatment when administered to this specific subtype of PCOS and supports the use of targeted nutraceutical therapy as an alternative to conventional treatments, especially in non-hyperandrogenic PCOS patients. Full article

Polycystic ovary syndrome (PCOS) is a complex disorder characterized by reproductive abnormalities such as hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology, and is frequently accompanied by metabolic disturbances such as insulin resistance, obesity and dyslipidemia. Genome-wide association studies (GWASs) have identified several susceptibility loci, yet little is known about their functional implications. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9) has emerged as a powerful gene editing tool in bridging this gap by allowing researchers to directly target candidate genes in ovarian and metabolic pathways. For instance, experimental models have highlighted the role of CYP17A1 and DENND1A.V2 in androgen excess, anti-Müllerian hormone (AMH) in follicular arrest, and insulin receptor substrate 1 (IRS1) and PPARγ in insulin signaling and adipogenesis. To highlight the multifactorial nature of PCOS, animal models, including zebrafish and rodents, have been used to reveal interactions between reproductive and metabolic phenotypes. Nevertheless, most studies remain restricted to single-gene models, and dual-gene models or combined gene editing and hormonal induction models remain underexplored. Future research integrating precision editing, multi-omic platforms, and patient-derived organoids may provide more accurate disease models and novel therapeutic strategies. Full article

Introduction: Polycystic ovary syndrome (PCOS) is associated with obesity, numerous metabolic complications, and an increased risk of cardiovascular disease. Adipokines, secreted by adipose tissue, may contribute to the development of these cardiometabolic disturbances. The aim of this study was to investigate the adipokine levels and their relationship with metabolic status in adolescent girls with PCOS. Patients and Methods: This cross-sectional study included 66 adolescent girls with PCOS (mean age: 16.5 ± 1.08 years; study group, SG) and 30 regularly menstruating girls (mean age: 16.2 ± 1.37 years; control group, CG) recruited between 2012 and 2017. All participants underwent physical examination, body composition assessment, liver ultrasonography, and biochemical and hormonal evaluations. Fasting venous blood samples were collected to determine the adipokine profile, and the leptin-to-adiponectin ratio (L/A) was calculated. Results: Compared with the control group, the PCOS group demonstrated significantly lower adiponectin (p = 0.019) and vaspin (p = 0.037) concentrations, and higher RBP-4 levels (p = 0.048). Positive correlations were observed between adiponectin, apelin, and omentin, while negative correlations were found between leptin and L/A and HDL cholesterol levels in the SG. Omentin showed a negative association, and leptin and L/A a positive association, with triglyceride concentration. In the SG, resistin and visfatin levels were negatively correlated with total cholesterol, and resistin also showed a negative correlation with LDL cholesterol. In patients with PCOS, adverse associations were observed between carbohydrate metabolism parameters and insulin resistance indices, while insulin sensitivity indices correlated positively with adiponectin and omentin concentrations. Visfatin levels in the SG correlated negatively with QUICKI. Conclusions: The adipokine profile of adolescent girls with PCOS differs from that of regularly menstruating peers, particularly in adiponectin, RBP-4, and vaspin concentrations. However, the absence of significant correlations between RBP-4 and vaspin and lipid or carbohydrate metabolism parameters suggests that these adipokines are not reliable markers of metabolic disturbances in adolescent girls with PCOS. Full article

Obesity has become increasingly prevalent, impacting up to 41 percent of women in the United States between 2021 and 2023, leading to a rise in short- and long-term adverse health events. With regard to reproductive health, obesity is associated with menstrual irregularities, poorer reproductive and obstetric outcomes, and an increased risk of endometrial cancer. Obesity can lead to hyperandrogenism and anovulation, which is consistent with polycystic ovarian syndrome (PCOS). The prevalence of obesity is higher in women with PCOS compared to the general population. Although PCOS increases the risk of obesity, not all women with PCOS are obese, and not all women with obesity develop PCOS. However, individuals with both PCOS and obesity often present with a more extreme phenotype, with increased risk of chronic anovulation, glucose intolerance, dyslipidemia, metabolic syndrome, vitamin D deficiency, and decreased fertility. Therefore, weight loss is the backbone of patient management in women with obesity and PCOS, and is associated with improvement in cardiovascular risk, as well as improvement in menstrual cycles, ovulation, and pregnancy rate. Lifestyle modifications are often the first-line intervention, with data supporting low glycemic index diets, including ketogenic and DASH diets, along with vitamin D supplementation to improve hormonal imbalances, insulin sensitivity, and menstrual cycles in those who do not have normal vitamin D levels. Furthermore, with the recent widespread adoption of newer FDA-approved medications for weight loss, including GLP-1 (glucagon-like peptide) receptor agonists, new data are emerging regarding the impact of PCOS and longer-term cardiovascular risk. The treatment of PCOS requires a personalized approach, with consideration of a patient’s reproductive goals, tolerance of risk, and acceptance of behavioral and financial commitments, as well as consideration of other medical comorbidities. This narrative review explores different weight loss treatment options, comparing lifestyle modifications (including diet, physical activity, mindfulness, stress management, and cognitive behavioral training), weight loss medications, and bariatric surgery and their respective impact on PCOS to assist clinicians in guiding their patients towards an effective, individualized intervention. Full article

Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder affecting 6–20% of women of reproductive age, manifesting through hyperandrogenism, ovulatory dysfunction, insulin resistance, and diverse metabolic derangements. Increasing evidence highlights the contribution of environmental factors, particularly endocrine-disrupting chemicals (EDCs), to PCOS susceptibility and severity. Sunscreen ultraviolet (UV) filters such as oxybenzone (benzophenone-3) and octinoxate (ethylhexyl methoxycinnamate) are widely used EDCs with established systemic absorption and biomonitoring evidence in human populations. Their endocrine-disrupting potential encompasses estrogenic and anti-androgenic activity, interference with steroidogenic enzymes, modulation of thyroid hormone, induction of oxidative stress, and epigenetic reprogramming, all of which are mechanistic pathways that overlap with PCOS pathophysiology. This evidence-based study critically appraises the evidence linking oxybenzone and octinoxate exposures to ovarian endocrinology, with a PCOS-specific focus. Human exposure patterns, pharmacokinetics, and regulatory perspectives are summarized alongside preclinical and in vitro data implicating these filters in ovarian dysfunction. Mechanistic intersections with PCOS include hyperandrogenism, disrupted folliculogenesis, oxidative stress-adipokine imbalance, and potential impairment of vitamin D signaling. Although epidemiological studies directly addressing PCOS outcomes remain sparse, the convergence of toxicological evidence with known endocrine vulnerabilities in PCOS underscores a need for targeted investigation. By mapping exposure pathways and mechanistic disruptions, this appraisal emphasizes the translational relevance of UV filter toxicity in the context of PCOS. It advocates for PCOS-specific biomonitoring cohorts, mechanistic studies, and regulatory consideration of reproductive endpoints while balancing the dermatological benefits of photoprotection against reproductive risks. Full article

Polycystic ovary syndrome (PCOS) represents one of the most prevalent endocrine–metabolic disorder in women of reproductive age, which includes but not restricted to reproductive disruptions, insulin resistance (IR), hyperandrogenism, and chronic low-grade inflammation. Its heterogeneous pathophysiology arises from the interplay of metabolic, endocrine, and immune factors, including dysregulated adipokine secretion, cytokine-mediated inflammation, oxidative stress (OS), and mitochondrial dysfunction. Current pharmacological therapies, such as metformin, clomiphene, and oral contraceptives, often provide partial benefits and are limited by side effects, necessitating the exploration of safer, multi-target strategies. Flavonoids, a structurally diverse class of plant-derived polyphenols, have gained attention as promising therapeutic candidates in PCOS due to their antioxidant, anti-inflammatory, insulin-sensitizing, and hormone-modulating properties. Preclinical studies in rodent PCOS models consistently demonstrate improvements in insulin sensitivity, normalization of ovarian morphology, restoration of ovulation, and reduction in hyperandrogenism. Human clinical studies, though limited in scale and heterogeneity, report favorable effects of flavonoids such as quercetin, isoflavones, and catechins on glucose metabolism, adipokine balance, inflammatory markers, and reproductive functions. This evidence-based study critically synthesizes mechanistic insights into how flavonoids modulate insulin signaling, adipokine–cytokine crosstalk, OS, and androgen excess, while highlighting translational evidence and emerging delivery systems aimed at overcoming bioavailability barriers. Collectively, flavonoids represent a promising class of nutraceuticals and adjuncts to conventional therapies, offering an integrative strategy for the management of PCOS. Full article

Background: Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. The apoptosis of granulosa cells (GCs) is strongly associated with the impaired follicular development in PCOS. The underlying mechanisms, however, remain incompletely elucidated. A significant increase in circulating lactic acid, an anaerobic respiration product, has been detected in PCOS patients. Yet, alterations in local ovarian lactic acid levels and their impact on GCs remain unknown. Methods: PCOS mouse models were established via 20-day daily subcutaneous dehydroepiandrosterone (DHEA) injections. In vitro experiments utilized DHEA-treated KGN cells to mimic hyperandrogenic conditions. Circulating, ovarian, and cellular lactic acid concentrations were quantified. Intracellular and extracellular pH values were measured using BCECF-AM fluorescent probe and a blood gas analyzer, respectively. Apoptosis was assessed through both flow cytometry and TUNEL assay. The antioxidant N-acetylcysteine (NAC) was used to investigate its effects on lactic acid levels and the subsequent GC apoptosis. Results: High androgen levels caused mitochondrial damage, promoted anaerobic glycolysis and led to lactic acid accumulation, inducing decreased intracellular pH and thus apoptosis of GCs. The antioxidant NAC effectively alleviated oxidative stress, mitigated mitochondrial damage, and decreased lactic acid levels and apoptosis in KGN cells. In PCOS mice, NAC improved ovarian morphology, but it did not affect the estrous cycle of the mice. Conclusions: Hyperandrogenemia-induced mitochondrial dysfunction caused the accumulation of lactic acid and thus apoptosis of ovarian GCs in PCOS mice. NAC enhanced mitochondrial function, consequently decreasing lactic acid concentrations. These findings suggest novel therapeutic targets for PCOS. Full article

Background: Polycystic ovarian syndrome (PCOS) is one of the most prevalent reproductive, endocrine, and metabolic disorders inflicting women of childbearing age. Dietary interventions have gained interest as non-pharmacological approach to control obesity and metabolic disturbances. However, the effects of intermittent fasting (IF) on metabolic and hormonal profiles of PCOS patients is debatable. Objectives: We performed this systematic review and meta-analysis to explore IF’s effect on PCOS women’s metabolic and hormonal profile (PROSPERO: CRD42024511520). Eligible studies included IF interventions in women with PCOS, with metabolic and hormonal profiles being reported. Methods: A systematic literature search using three databases, including PubMed, SCOPUS, and Web of Science, was conducted. The systematic review was performed following PRISMA guidelines. Results: A total of four studies were included (N = 4). IF is not associated with significant change in BMI (MD = −0.200, 95% CI [−0.807, 0.407], p = 0.518). The analysis revealed that IF had no statistically significant impact on FBG (MD = −0.569, 95% CI [−9.955, 8.818], p = 0.906), HOMA-IR (MD = −0.862, 95% CI [−1.737, 0.014], p = 0.054), and FINS (MD = −2.749, 95% CI [−6.441, 0.943], p = 0.145). No significant change in TG (MD = −3.120, 95% CI [−9.624, 3.385], p = 0.347), total cholesterol (MD = −0.918, 95% CI [−2.960, 1.124], p = 0.378), and LDL levels (MD = −0.433, 95% CI [−1.224, 0.359], p = 0.284) between IF and pre-fasting or non-intervention diet groups. However, the explanation is limited by the small number of studies, duration of fasting regimes, and/or variations in fasting strategies. Sex hormone data were collected but were insufficient for a pooled analysis. Conclusions: Overall, our study suggests that IF is not an effective intervention to enhance BMI, glycaemic control, and lipid metabolism in PCOS patients. Nevertheless, the current conclusion is inconclusive and preliminary, as additional well-designed studies are required to support this conclusion. Full article

Objectives: This study aimed to evaluate the effects of thymoquinone (TMQ) on metabolic, hormonal, and ovarian dysfunctions in a letrozole-induced polycystic ovary syndrome (PCOS) rat model and compare its efficacy with metformin, which is widely recognized as the first-line pharmacological treatment for PCOS. Methods: Thirty-two female Wistar Albino rats were randomly assigned into four groups: control (I), PCOS (II), PCOS + metformin (III), and PCOS + Thymoquinone (IV). PCOS was induced using 1 mg/kg/day letrozole for 21 days, followed by treatment with either metformin (500 mg/kg/day) or thymoquinone (50 mg/kg/day) for 30 days. Metabolic (glucose, insulin, HOMA-IR, lipid profile), hormonal (estrone, estradiol, testosterone, androstenedione), and histopathological parameters were assessed. Results: PCOS induction resulted in significant metabolic, hormonal, and ovarian dysfunctions. Final body weight was significantly higher in PCOS (309.0 ± 7.5 g) vs. control (275.3 ± 8.2 g, p < 0.001), but reduced by metformin (294.0 ± 7.4 g, p < 0.01) and thymoquinone (305.7 ± 7.5 g, p < 0.01). Glucose levels were significantly elevated in PCOS (341.8 ± 16.8 mg/dL) vs. control (260.0 ± 15.8 mg/dL, p < 0.01), while metformin (290.2 ± 19.7 mg/dL, p < 0.05) and thymoquinone (320.3 ± 13.7 mg/dL, p < 0.05) reduced glucose levels. Insulin and HOMA-IR were significantly increased in PCOS (p < 0.001), but reduced by both treatments (p < 0.01). Lipid profile improvements were observed, with significant reductions in TG and LDL-C and increases in HDL-C in both treatment groups (p < 0.05–0.01). PCOS induced hyperandrogenism, with increased testosterone and androstenedione (p < 0.05), and a decreased E2/E1 ratio (p < 0.001), which were significantly improved by metformin and thymoquinone (p < 0.01). Ovarian histopathology showed increased cystic and atretic follicles and reduced corpus luteum in PCOS (p < 0.05–0.01), which were significantly improved by both treatments. Conclusions: TMQ exerts metabolic, hormonal, and ovarian protective effects comparable to metformin, supporting its potential as a natural therapeutic alternative for PCOS management. Given that metformin is already established as a first-line pharmacological therapy, our findings suggest that TMQ may provide a promising complementary or alternative approach. Further clinical studies are warranted to evaluate its safety and efficacy in human PCOS patients. Full article