Metformin as a Neuroendocrine Modulator in Catamenial Epilepsy: Interplay with Sex Hormones and Neurosteroids

Catamenial epilepsy (CE) is a hormone-sensitive neurological condition characterized by the cyclical exacerbation of seizures in relation to the menstrual cycle. This condition arises from fluctuations in sex hormones, particularly elevated estrogen and diminished progesterone levels, which disrupt the excitatory-inhibitory balance within the brain. Neurosteroids, such as allopregnanolone, which modulate GABAergic signaling, also play a critical role in seizure susceptibility and resistance. Conventional anti-seizure medications often provide limited benefit in CE, emphasizing the need for novel therapeutic approaches. Metformin, a widely used antidiabetic agent, exhibits neuromodulatory properties that extend beyond glycemic control. This review discusses the potential repurposing of metformin in the management of CE, focusing on its regulatory effects on estrogen and progesterone levels, as well as its capacity to restore neurosteroid signaling. Metformin's influence on AMPK/mTOR pathways, neuroinflammation, and GABAergic neurotransmission positions it as a promising adjunctive therapy for hormone-related seizure disorders. This work highlights metformin's emerging role as a neuroendocrine modulator and its therapeutic potential in addressing the pathophysiological triad of CE: estrogen excess, progesterone deficiency, and neurosteroid imbalance. Thus, this review discusses the potential repurposing of metformin in the management of CE, focusing on its regulatory effects on estrogen and progesterone levels, as well as its capacity to restore neurosteroid signaling.