Polycystic ovarian syndrome (PCOS) is the most prevalent metabolic cum endocrine dysfunction (Norman et al., 2007). PCOS is a prevalent with global estimates ranging from 6 to 20 % depending on diagnostic criteria and population differences (Salari et al., 2024). The broader Rotterdam criteria report higher prevalence rates (up to 20 %), while the stricter NIH criteria suggest a lower rate (around 6–10 %) (Neven et al., 2024; Stener-Victorin et al., 2024). Regionally, PCOS affects 6–12 % of women in the U.S., 9–22 % in India, and up to 25 % in Middle Eastern countries, often linked to genetic factors, lifestyle, and higher obesity rates (Alkhezi et al., 2024; Ganie et al., 2024). The manifestation of the syndrome ranges from hormonal imbalance to absolute infertility, and the significant hormonal anomalies of hyperinsulinemia and hyperandrogenemia (Diamanti-Kandarakis and Dunaif, 2012; Lim et al., 2012). Hyperinsulinemia further fuels the vicious cycle in PCOS by stimulating androgen production and reduction of SHBG, which results in higher levels of free androgens (Diamanti-Kandarakis and Dunaif, 2012). Despite the detrimental effect of PCOS on women's health, the etiology of PCOS is not well understood, and hence effective therapeutics have not been introduced. Because of the involvement of genetic links and family accumulation traits identified for the progression of the disease, PCOS is a candidate for genomic analysis which can subsequently help in the development of its markers (Cloke and Christian, 2012). Recently genome-wide association studies (GWAS) established that YAP1 (Yes-associated Protein-1) have a substantial role in the pathogenesis of PCOS (Chen et al., 2011; Cui et al., 2013).

Furthermore, genes in the Wingless-related integration site (Wnt) pathway have been linked with the pathogenesis of PCOS, but the pathways stimulated by these genes are yet to be established (Dunlap et al., 2011; Liu et al., 2013; Savaris et al., 2011). In addition to this, researchers have found the role of the Wnt pathway in dysregulation of cellular differentiation and the expression of hormonal receptors on ovarian tissue, which plays a pivotal role in the pathogenesis of PCOS (Cheng and Xu, 2023). In concurrence with these findings, Wnt signaling has been found to be critical for reproductive functioning, which secondarily ameliorates sex hormone imbalance, thereby contributing to the pathophysiology of PCOS. Wnt7a, Wnt3a, Wnt8b and YAP1 have been identified to have significant role in pathogenesis of PCOS as these genes are involved in patterning, proliferation, and differentiation of endometrium (Savaris et al., 2011). Hence, elucidating the signal transduction pathways/biomarkers involved in PCOS pathophysiology will improve our understanding of modulating follicular growth and illuminate the correlation between PCOS and ovarian dysfunction, which can be further utilized in assisted reproduction techniques.

The pathogenesis of PCOS is complex and multifactorial, involving a wide array of genetic, hormonal, metabolic, and environmental risk factors (Sikiru et al., 2023). This complexity makes pinpointing key pathogenic drivers challenging, contributing to the difficulty in developing standardized management strategies. Traditionally, therapeutic approaches have focused primarily on reducing hyperandrogenism and alleviating symptoms such as menstrual irregularities and insulin resistance (Chang et al., 2024). Current management is instead highly individualized, tailored to the specific symptoms, patient needs, and severity of the condition, often requiring a combination of lifestyle interventions, pharmacotherapy, and, in some cases, surgical options (Jayasena and Franks, 2014; Palomba et al., 2015). A broad spectrum of medications has been used to ameliorate the clinical manifestation of PCOS, but most were found to be partially effective. For instance, insulin sensitizers like metformin and thiazolidinedione derivatives are often used to address PCOS. However, the morphological, genetic, and metabolic alterations induced by metformin in physiological and pathological contexts, notably the reproductive abnormalities allied with PCOS, have remained largely unknown. Importantly, recent studies have found LDS, is quite effective and secure. However, contradictory results have been found from their use in actual clinical settings (Alesi et al., 2023; Ganie et al., 2004, 2013). Based on these findings, we sought to (i) identify the phenotypic, hormonal, and genotypic determinants of the disease in laboratory animals of PCOS (Abbott et al., 2013; Caldwell et al., 2014; Ryu et al., 2019). (ii) Validate the biomarkers identified and their association with genomic determinants of the disease. (iii) Evaluate the therapeutic efficacy of LDS combined with an insulin sensitizer (metformin) and therapeutic validation based on amelioration of phenotypic, hormonal, and genotypic markers of PCOS.