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Gonadal hormone deprivation regulates response to tibolone in neurodegenerative pathways
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Abstract
Gonadal hormone deprivation (GHD) and decline such as menopause and bilateral oophorectomy are associated with an increased risk of neurodegeneration. Yet, hormone therapies (HTs) show varying efficacy, influenced by factors such as sex, drug type, and timing of treatment relative to hormone decline. We hypothesize that the molecular environment of the brain undergoes a transition following GHD, impacting the effectiveness of HTs. Using a GHD model in mice treated with Tibolone, we conducted proteomic analysis and identified a reprogrammed response to Tibolone, a compound that stimulates estrogenic, progestogenic, and androgenic pathways. Through a comprehensive network pharmacological workflow, we identified a reprogrammed response to Tibolone, particularly within "Pathways of Neurodegeneration", as well as interconnected pathways including "cellular respiration", "carbon metabolism", and "cellular homeostasis". Analysis revealed 23 proteins whose Tibolone response depended on GHD and/or sex, implicating critical processes like oxidative phosphorylation and calcium signalling. Our findings suggest the therapeutic efficacy of HTs may depend on these variables, suggesting a need for greater precision medicine considerations whilst highlighting the need to uncover underlying mechanisms.
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Elsevier
Citation
Journal of Steroid Biochemistry and Molecular Biology 241, 106520
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McGovern_2024_Gonadel.pdf
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Funding Information
Science Foundation Ireland under the Frontiers for the Future Programme (Grant #20/FFPP/8649) to GEB. This work was also supported by grant PID2020–115019RB-I00, awarded to M.A.A., from Agencia Estatal de Investigacion ´ (AEI), co-funded by Fondo Europeo de Desarrollo Regional (FEDER) and by Centro de Investigacion ´ Biom´edica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain