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Abstract
Background
The common endocrine disorder characterised by metabolic abnormalities, hyperandrogenism, and ovulatory dysfunction is polycystic ovary syndrome (PCOS). Natural phytoestrogens like Daidzein and Genistein show promise in modulating PCOS-related pathologies, but their clinical utility is limited by poor bioavailability.
Objectives
This study aimed to develop and evaluate nanoparticle (NP)-based formulations of Daidzein and Genistein to improve their therapeutic efficacy in a letrozole-induced PCOS rat model.
Methods
Daidzein and Genistein nanoparticles (NPs) were prepared using a single-emulsion solvent evaporation technique and optimised through a 32 full factorial design. Physicochemical characterisation included FTIR, DSC, XRD, particle size, zeta potential, and FE-SEM analyses. PCOS was induced in female Wistar rats using letrozole, followed by oral administration of combined Daidzein-Genistein nanoformulations at low (25 mg/kg) and high (50 mg/kg) doses for 35 days. Animals were divided into naïve control, PCOS control, standard treatment (Clomiphene citrate), and treatment groups. Therapeutic efficacy was evaluated by assessing oestrous cyclicity, body and ovarian weight, hormonal and lipid profiles, oral glucose tolerance, oxidative stress markers, pro-inflammatory cytokines, and ovarian histopathology.
Results
Optimised NPs demonstrated particle sizes of 198-450 nm and >90% entrapment efficiency. NP-treated groups showed significant restoration of oestrous cycles, reduced body and ovarian weight, and normalised hormone levels (LH, FSH, E2, TTST). There were notable improvements in insulin sensitivity, glucose tolerance, and lipid profiles. Markers of oxidative stress and inflammation, such as GSH, SOD, CAT, MDA, IL-6, and TNF-α, were modulated, while antioxidant enzymes and key regulators (SIRT1, PGC-1α) were upregulated. Histopathology confirmed improved follicular architecture.
Conclusion
Daidzein and Genistein NPs offer a potent, multi-targeted therapy for PCOS, outperforming plain drug formulations and demonstrating efficacy comparable to standard treatment. Nanotechnology-based delivery significantly enhances the bioefficacy of natural isoflavones, supporting their potential in PCOS management.
Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by ovulatory dysfunction, hyperandrogenism, and insulin resistance. It results from complex genetic and environmental factors and progressively impairs reproductive and metabolic health. Natural phytotherapy provides holistic regulation through multiple components and targets and is recognized for its favorable safety profile, including low organ toxicity. Consequently, it represents a promising avenue for comprehensive PCOS management. This review aims to comprehensively analyze the ethnopharmacological applications of natural herbs in modulating ferroptosis within the context of PCOS. This study systematically reviewed natural herbal interventions for PCOS, with a focus on their mechanisms in regulating ferroptosis. It consulted traditional medical classics, ethnomedicinal records, and clinical literature, and searched databases including PubMed and the China National Knowledge Infrastructure (CNKI). Keywords such as "PCOS," "ferroptosis," "natural herbal medicines," "traditional Chinese medicine (TCM) compound preparations," "single-herb extracts," and "plant active ingredients" were used to retrieve research from ethnobotany, phytochemistry, and pharmacology. Recent relevant publications were comprehensively collected and analyzed. Integrating natural herbal medicines into the comprehensive management of PCOS offers several advantages, which can be primarily explained from two perspectives. First, the pathological mechanisms of PCOS involve multiple interconnected biological processes, including hormonal imbalance, insulin resistance, oxidative stress, and chronic inflammation. The onset and progression of PCOS are closely linked to cell death pathways such as ferroptosis and are regulated by various molecular pathways, including GPX4/COX2, SLC7A11/GPX4, circ_0097636/miR-186-5p/SIRT3, and AMPK/Nrf2 signaling. Drugs targeting a single molecule often struggle to effectively regulate such a complex network. In contrast, various herbal medicines and their active components-such as platycodin D, nuciferine (NF), baicalein, and berberine (BBR)-exhibit multi-target properties, enabling them to simultaneously modulate key molecules involved in ferroptosis in PCOS, including GPX4, SLC7A11, COX2, FTH1, ACSL4, and ferritin. This allows for synergistic intervention in multiple pathological processes of the disease. Additionally, natural herbal medicines and their active components have demonstrated a high level of safety with long-term use, particularly exhibiting relatively lower risks of liver and kidney toxicity. They offer certain advantages compared to traditional hormones or insulin sensitizers. For example, classic compound prescriptions such as Wenshen Tiaojing decoction (WSTJD), Shoutai pill, and Erchen decoction are commonly used in TCM clinical practice to regulate menstruation, improve insulin resistance, and promote ovulation, supported by extensive practical evidence. In recent years, to clarify their scientific basis, an increasing number of studies have extracted key active components from these effective compound formulations using modern separation techniques. With the aid of cell and animal experiments, researchers have thoroughly elucidated the mechanisms by which these components improve PCOS through pathways such as the regulation of ferroptosis, thereby bridging traditional knowledge and modern pharmacology Traditional Chinese compound formulations hold significant promise for developing drugs targeting PCOS. Notably, certain prescriptions and herbal extracts that focus on regulating ferroptosis as a key mechanism are attracting increasing attention and research within the academic community.
Zhang D et al., 2026·International journal of women's health·Free full text on PubMed Central
Tamoxifen, clomiphene, and letrozole are primary pharmacological options for inducing ovulation in polycystic ovary syndrome (PCOS). Given the high clinical prevalence of PCOS, a comprehensive characterization of the adverse drug event (ADE) profiles associated with these treatments is essential. We performed disproportionality analyses using FAERS data to detect ADE signals at the Preferred Term (PT) and System Organ Class (SOC) levels via four established algorithms (ROR, PRR, BCPNN, and EBGM). A drug-ADE network was constructed to visualize these associations. Of 21,730 identified PCOS-related reports, letrozole predominated (n=17,185), followed by tamoxifen (n=4465) and clomiphene (n=80). Most cases involved women aged 18-65 years (weight: 50-100 kg), primarily from the United States. Letrozole-related reports increased steadily, peaking at 2323 cases in 2021, while tamoxifen and clomiphene counts remained comparatively low. At the PT level, fatigue was a common signal for both tamoxifen and letrozole. Notably, malignant tumor progression, fatigue, and arthralgia emerged as shared signals across all three agents. At the SOC level, ADEs for tamoxifen and letrozole were frequently categorized under neoplasms; letrozole was specifically linked to hematological disorders (e.g, neutropenia). In contrast, clomiphene exhibited stronger associations with psychiatric and gastrointestinal events. Distinct safety signals characterize these three primary PCOS treatments. These pharmacological variations underscore the necessity of personalized medicine; treatment selection must be tailored to the patient's specific risk profile, with targeted clinical monitoring for relevant ADEs to optimize therapeutic outcomes.
Costello MF et al., 2019·Aust N Z J Obstet Gynaecol
Polycystic ovary syndrome (PCOS) is complex with reproductive, metabolic and psychological features. Infertility is a prevalent presenting feature of PCOS with approximately 75% of these women suffering infertility due to anovulation, making PCOS by far the most common cause of anovulatory infertility. Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. This review paper aims to provide a brief update on the best available and most current research evidence supporting the treatment of PCOS which informed the recommendations in the assessment and treatment of infertility section of the international evidence-based guideline on PCOS 2018. International evidence-based guideline development engaged professional societies and consumer organisations with multidisciplinary experts and women with PCOS directly involved at all stages. Lifestyle change alone is considered the first-line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. Letrozole should now be considered first-line pharmacological treatment for ovulation induction to improve fertility outcomes. Clomiphene citrate alone and metformin alone could also be used as first-line pharmacological therapy, although both are less effective than letrozole and metformin is less effective than clomiphene citrate in obese women. Gonadotrophins or laparoscopic ovarian surgery are usually second-line ovulation induction therapies. In the absence of an absolute indication for in vitro fertilisation (IVF) / intracytoplasmic sperm injection, women with PCOS and anovulatory infertility could be offered IVF as third-line therapy where firstor second-line ovulation induction therapies have failed. This review provides the best available evidence informing recommendations (along with clinical expertise and consumer preference) which provide clinicians with clear advice on best practice for the management of infertile women with PCOS.
Metabolic and Endocrine Agents · Insulin Sensitizing Agents
Duleba AJ, 2012·Steroids·Free full text on PubMed Central
Polycystic ovary syndrome (PCOS) is associated with metabolic derangements including insulin resistance, dyslipidemia, systemic inflammation and endothelial dysfunction. There is a growing need to develop pharmacologic interventions to improve metabolic function in women with PCOS. Medications that have been tested in patients with PCOS include metformin, thiazolidinediones, acarbose, naltrexone, orlistat, vitamin D and statins. Metformin decreases hepatic gluconeogenesis and free fatty acid oxidation while increasing peripheral glucose uptake. Early studies in PCOS suggested that metformin indirectly reduces insulin level, dyslipidemia and systemic inflammation; however, recent placebo-controlled trials failed to demonstrate significant metabolic benefit. Thiazolidinediones act primarily by increasing peripheral glucose uptake. Most studies in PCOS have demonstrated that thiazolidinediones reduce insulin resistance; however, effects on dyslipidemia were disappointing. Use of thiazolidinediones is associated with weight gain and major complications. Acarbose reduces digestion of polysaccharides. Studies in PCOS yielded inconsistent effects of acarbose on insulin sensitivity and no significant improvement of dyslipidemia. Naltrexone reduces appetite and modulates insulin release; its use in PCOS may reduce hyperinsulinemia. Orlistat decreases absorption of dietary fats; studies in PCOS suggest beneficial effects on insulin sensitivity. Vitamin D may improve insulin sensitivity but mixed results on lipid profile in PCOS have been reported. Statins are competitive inhibitors of the key enzyme regulating the mevalonate pathway; their effects are related to reduced cholesterol production as well as anti-inflammatory and anti-oxidant properties. In women with PCOS, statins reduce hyperandrogenism, improve lipid profile and reduce systemic inflammation while the effects on insulin sensitivity are variable. Use of statins is contraindicated in pregnancy.
Neelam L Dashputre, Umesh D Laddha, Nayana K Patil, Vishal D Dhopare
N Dashputre, U Laddha, N Patil, V Dhopare
PMID 42297265 42297265 DOI 10.1016/j.nano.2026.102975 10.1016/j.nano.2026.102975 Dashputre et al. 2026, Dashputre 2026