Diosgenin in polyendocrine metabolic ovarian syndrome: modulation of insulin resistance, inflammation, steroidogenesis, and metabolic dysfunction

Polyendocrine Metabolic Ovarian Syndrome (PMOS) is a complex endocrinopathy with characteristic features of hyperandrogenism, ovulatory dysfunction, insulin resistance, and obesity, accompanied by other associated metabolic conditions, such as chronic inflammation, oxidative stress, and dyslipidemia. Currently available treatment options are metformin and thiazolidinediones, which address only the individual symptoms but associated with adverse side effects and variable outcomes. Therefore, the establishment of multi-targeted therapeutic advances remains elusive in managing the multifactorial complications of PMOS. Intriguingly, diosgenin, a steroidal sapogenin moiety abundantly present in Dioscoreaceae spp. has gained significant interest for its multimodal effects, including insulin sensitization and regulation of ovarian steroidogenesis, owing to its antioxidant, anti-inflammatory, and hypolipidemic properties. This review discusses the role of diosgenin in regulating the pathways, including PI3K/AKT, NF-κB, lipid homeostasis, and steroidogenesis, that are primarily disrupted in PMOS. In fact, a nuclear transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), acts as an upstream element of this vital regulatory machinery. Emerging evidence suggests that targeting PPARγ with diosgenin may improve insulin resistance, granulosa cell survival, and aromatase activity. This review presents the available preclinical and clinical evidence, as well as the challenges associated with the delivery, bioavailability, and future translational aspects of diosgenin in the management of PMOS. In summary, diosgenin may emerge as a multi-target candidate for the treatment of PMOS; however, its clinical translation requires mechanistic validation of PPARγ-mediated signaling, addressing inconsistencies in preclinical findings, optimizing bioavailability, and conducting well-designed clinical trials to establish its safety and therapeutic efficacy.