The Estrogen-Mitochondria Axis in Bipolar Disorder: From Fluctuating Hormones to Failing Bioenergetics

Bipolar disorder (BD) is a psychiatric illness marked by fluctuating mood states and substantial systemic consequences, including dysregulated bioenergetics, immune modulations, and significant metabolic dysfunction. Although BD affects males and females at comparable rates, the literature indicates that the symptomatology and course of the disorder can differ between sexes. Females with BD are more likely to exhibit rapid cycling and depressive symptoms, whereas in males BD is more frequently associated with reckless behavior and hallucinations. A plausible mechanism for these symptomatology differences may be marked by the estrogen-mitochondria axis, which reflects the bioenergetic consequences of fluctuating estrogen levels on mitochondrial biogenesis (MB). Estrogen constitutes a family of steroid hormones that have critical regulatory roles in many physiological processes, including reproduction, metabolism, and immune regulation. In the context of bioenergetics, estrogen supports mitochondrial function in neural tissue by promoting oxidative phosphorylation, reducing oxidative stress, and regulating MB. In this literature review, we examine evidence linking estrogen fluctuation to periods of psychiatric vulnerability across the life span in females with BD. There is a particular focus on the mechanistic role of estrogen modulating MB, the existing experimental and preclinical evidence underlying this mechanism, and the evaluation of current pharmacological and nutraceutical therapeutics that have the potential to modulate this axis. Finally, we discuss the clinical and future therapeutic implications for behavioral symptomatology across the life span of females with BD. While this review focuses solely on literature on BD, the plausibility of investigating this mechanism extends to other mood disorders and psychiatric diseases.