Hormone therapy in precision medicine: a preclinical exploration of interactions between tibolone, sex, and gonadal hormone deprivation in the brain

Neurological diseases often impact females more significantly than males, with sex hormone fluctuations, such as those occurring during menopause, playing a substantial role. Despite known connections, the mechanisms through which sex hormones influence brain function and their modulation by hormone therapies like Tibolone remain insufficiently explored. This thesis aims to address these knowledge gaps by investigating the interactions between biological sex, gonadal hormone deprivation, and Tibolone in the murine prefrontal cortex (PFC)—a region both vulnerable to neurodegenerative diseases and responsive to sex hormone action.

Utilizing a murine model, male and female mice were subjected to gonadectomy, followed by acute Tibolone treatment. Comprehensive proteomic analyses of the PFC were conducted to identify changes in the protein landscape influenced by sex, gonadectomy, and Tibolone. Findings reveal that biological sex and the presence or absence of gonadal hormones significantly alter Tibolone's impact on key pathways, including mitochondrial metabolism, oxidative phosphorylation, and synaptic function. Differential protein expression patterns highlight the complex regulatory roles of sex hormones and their interactions with Tibolone, which impact neurodegeneration-related pathways.

Proteomic data further demonstrated that sex and gonadal status modulate the efficacy of Tibolone in neurodegenerative contexts. Key proteins involved in mitochondrial function, such as NDUFA2, NDUFA7, and UQCR10, showed significant sex-specific alterations, indicating that mitochondrial bioenergetics may underlie observed sex differences in neurodegenerative disease susceptibility. Additionally, geometric analyses confirmed sex-specific Tibolone responses, suggesting proteomic convergence following gonadal hormone deprivation.

This work underscores the critical role of sex-specific factors in hormone therapy outcomes and advocates for precision medicine approaches tailored to individual hormonal profiles. While focused on the PFC, the findings provide valuable insights into hormone therapy mechanisms, with implications for developing effective sex-specific interventions for neurodegenerative diseases.