Abstract: Context Premature ovarian insufficiency (POI) is a multifactorial syndrome developing in women under the age of 40, characterized by the loss of ovarian function, hypergonadotropic hypogonadism, and infertility. Mitochondrial dysfunction of granulosa cells, triggered by oxidative stress and leading to apoptosis, is recognized as a key mechanism in the pathogenesis of POI. Current therapeutic approaches, including hormone replacement therapy, are aimed at symptom management but fail to restore the ovarian reserve. A promising direction involves the use of agents activating the NRF2/HO-1 signaling pathway, which contributes to the restoration of mitochondrial homeostasis. Objective: to establish a reproducible cellular model of POI and to evaluate the therapeutic potential of omaveloxolone (RTA 408). Methods: a culture of ovarian granulosa cells obtained from Wistar rats was used after five passages. Mitochondrial dysfunction was induced by exposure to cyclophosphamide (0.1 mg/mL, 6 hours). In the experimental group, omaveloxolone (2 µL/mL) was added to the culture medium one hour after the start of incubation. The control group was cultured without any treatment. The morphology of the mitochondrial network, mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) production, and reduced glutathione levels were assessed using fluorescent probes and confocal microscopy. Results Exposure to cyclophosphamide caused significant alterations in the mitochondrial network and a reduction in ΔΨm, accompanied by increased ROS production and depletion of the glutathione pool. In the experimental group, omaveloxolone treatment significantly decreased ROS levels (67.7 ± 10.8% vs. 170 ± 21.4% in the untreated group, p < 0.05) and increased reduced glutathione levels (2730.94 ± 452.11% vs. 1230.64 ± 354.21%, p < 0.05), approximating the values observed in the control group. Conclusion Further studies are required to evaluate the efficacy and safety of this therapeutic approach in clinical practice. The proposed method may expand the range of treatment options for POI, providing an alternative to hormone-modulating therapy and surgical interventions, thereby reducing associated side effects and complications. Moreover, RTA 408 may serve as an adjuvant therapy aimed at preserving the ovarian reserve.

Cite: Yarmolinskaya M.I. , Zakuraeva K.A. , Pogonyalova M.Y.
Omaveloxolone (RTA 408) as a Novel Therapeutic Approach for Premature Ovarian Insufficiency via Modulation of Granulosa Cell Mitochondrial Function
The 20th IMS World Congress on Menopause 30 Sep - 3 Oct 2026