Hyperandrogenism Decreases Seizure Threshold in a Rat Model of Polycystic Ovary Syndrome.

Introduction: In women of childbearing age with epilepsy, 30% experience the comorbidity of polycystic ovary syndrome (PCOS), which is marked by a higher prevalence of hyperandrogenism. Our recent clinical observations indicate the potential contribution of hyperandrogenism-induced PCOS to epilepsy susceptibility, and this study aimed to unravel the underlying factors that increase the susceptibility of females to epilepsy. Methods: A letrozole-induced PCOS rat model was employed to simulate endogenous hyperandrogenism. The threshold of seizure was assessed through seizure kindling rates using pentetrazol and electroencephalogram recordings. Additionally, the role of androgens in epilepsy was verified through interventions using Diane-35. Results: This study revealed that letrozole-induced elevated testosterone levels and PCOS-related changes in female rats. PCOS rats, through pentetrazol-kindling, exhibited a reduced seizure threshold compared with controls. Elevated testosterone levels were observed in both the hippocampal and frontal brain tissues, accompanied by changes in circulation. Two weeks of Diane-35 intervention showed a tendency to alleviate these changes, modifying testosterone levels in both the plasma and brain tissue. Western blotting and immunohistochemistry revealed increased expression of GABA-A receptor in the hippocampus and decreased AMPA receptor expression in the frontal cortex, correlating with antiepileptic status in PCOS rats. Conclusion: This study delves into the impact of elevated androgen levels on seizure threshold, providing crucial insights into the underpinnings of the comorbidity between PCOS and epilepsy. These findings significantly contribute to the evolving field of epilepsy research, emphasizing the imperative consideration of hormonal influences for the development of targeted therapeutic interventions in individuals with epilepsy and PCOS. Plain Language Summary: This study looked at how a condition called polycystic ovary syndrome (PCOS), which involves higher levels of testosterone, is related to a comorbidity with epilepsy in women. They used female rats to mimic PCOS and raised their hormone levels using a drug called letrozole. Then we tested how easy these rats were kindled to seizures compared to normal rats and recorded their brain activity using electroencephalograms. We also used a common medication in PCOS, called Diane-35, to see if it could change the effects of the high testosterone levels on seizures. The results showed that the rats with PCOS-like symptoms had lower seizure thresholds and higher levels of certain hormones in their brains and blood. When they used Diane-35, the reduced testosterone in the brain affects neuronal signaling receptors, which could be linked to antiepileptic effect. Overall, this research suggests a connection between high hormone levels seen in PCOS and decreased threshold to seizures. Understanding this link could be important in developing specific treatments for people who have both epilepsy and PCOS. [ABSTRACT FROM AUTHOR]