The Role of Estrogen and Testosterone in Determining Brain Blood Flow and Metabolic Regulation in Humans

Summary

Due to historical exclusion of females from research, there are gaps in the understanding of female physiology, how it differs from males, and how sex-specific hormones contribute. As a result, many diagnoses and treatments are based on male physiology and may not be appropriate or effective for females. Females consistently experience greater risk and report worse neurological outcomes in many diseases, including stroke, cardiac arrest, and dementia. As research in females progresses, differences between sexes and changes throughout the lifespan (e.g., puberty, menopause) highlight the importance of understanding the effects of sex and sex-specific hormones on the body. The brain is arguably the most important organ in the body, consuming 20% of the body's total energy. Previous research supports higher blood flow to the brain in females, and research in animals suggests hormones such as estrogen, progesterone, and testosterone are responsible. However, it is extremely difficult to isolate these hormones in humans, due to natural fluctuations (i.e., menstrual cycle). Therefore, the investigators plan to explore the direct role of these sex-specific hormones in regulating blood flow to the brain by blocking hormone production in healthy males and females and giving back testosterone and estrogen, respectively. The investigators will then conduct a range of tests to look at blood flow to the brain at rest and during various stressors. This research will provide crucial insight into how males and females differ in regulation of brain blood flow and inform new treatments and therapies to a wide range of brain injuries and diseases, improving outcomes and reducing the sex disparity in clinical pathways.

Timeline

Start

2026-04-01

Primary completion

2026-12-31

Completion

2027-12-31

Publications

• Background Muer JD, Didier KD, Wannebo BM, Sanchez S, Khademi Motlagh H, Haley TL, Carter KJ, Banks NF, Eldridge MW, Serlin RC, Wieben O, Schrage WG. Sex differences in gray matter, white matter, and regional brain perfusion in young, healthy adults. Am J Physiol Heart Circ Physiol. 2024 Oct 1;327(4):H847-H858. doi: 10.1152/ajpheart.00341.2024. Epub 2024 Aug 9.
• Background Reeves MJ, Bushnell CD, Howard G, Gargano JW, Duncan PW, Lynch G, Khatiwoda A, Lisabeth L. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol. 2008 Oct;7(10):915-26. doi: 10.1016/S1474-4422(08)70193-5. Epub 2008 Aug 21.
• Background Moreau KL, Hildreth KL, Klawitter J, Blatchford P, Kohrt WM. Decline in endothelial function across the menopause transition in healthy women is related to decreased estradiol and increased oxidative stress. Geroscience. 2020 Dec;42(6):1699-1714. doi: 10.1007/s11357-020-00236-7. Epub 2020 Aug 8.

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