Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that progresses through repeated impacts. While often studied in male athletes, emerging evidence suggests that female athletes face unique, cyclical vulnerabilities that are tied to hormonal change during their menstrual cycle [1]
The Late Luteal Phase:
In contact sports like rugby, boxing, and football, female athletes experience a recurring period of heightened neurobiological vulnerability each month: the late luteal phase, which typically occurs between days 25 to 28 of the menstrual cycle, just before menstruation begins.
Figure 1: Schematic of the Menstrual Cycle Showing Dual Hormone Withdrawal During the Late Luteal Phase
During this phase, two critical neuroprotective hormones, estrogen and progesterone, decline sharply and simultaneously. This combined loss removes critical layers of protection, leaving neurons more fragile and less able to recover from brain injuries [2].
Estrogen: The Antioxidant Shield
Estrogen acts as the brain’s antioxidant and regulator. It reduces inflammation, boosts glutamate reuptake, and maintains calcium balance inside the neurons. When estrogen levels fall, the defence collapses, oxidative stress rises, calcium regulation falters, and neurons become more excitable and energy demanding.
If head impact occurs during this low hormone phase, the brain is already stretched thin, increasing injury’s effects and slowing recovery [1], [3].
Progesterone: The Inhibitory Brake
Progesterone is metabolised into allopregnanolone (ALLO), a compound that boosts GABA, the brain’s main inhibitory neurotransmitter. GABA acts like a brake system and keeps neural activity from running out of control [4].
When progesterone level drops sharply, ALLO and GABA activity declines. Without this, inhibition weakens, and neurons must expend more energy to maintain stability. This extra effort increases neuron stress and leaves the brain more vulnerable to additional stress, such as collision or concussion [5].
GABA Under Pressure and Amygdala Activation
Brain scans show that the GABA activity decreases during the late luteal phase, forcing the brain to work harder to stay calm. During this phase, the amygdala, the part of the brain responsible for emotional regulation and stress responses, also suffers from this hormone dip. Without its usual estrogen and progesterone shield, it becomes hyperreactive and a vulnerable target for injury when impact occurs.
CTE Progression May Follow the Menstrual Rhythm
For female athletes, the risk from head impact is not uniform; it fluctuates with hormonal cycles. Impact that occurs during the late luteal phase may cause disproportionately more damage compared to the same impact at another time of the menstrual cycle.
Declining hormone levels, particularly during menopause, are associated with cognitive decline, neuronal loss, and increased risk of neurodegenerative diseases such as CTE and Alzheimer’s disease [6].
These factors combined, the odds may not be in favour of female athletes in contact sports. It can be hypothesised that in the coming decades, older generations of female athletes may show higher rates of CTE and other neurodegenerative conditions unless proactive measures that factor in hormone fluctuations are implemented [7].
Figure 2: Late Luteal Phase CTE Vulnerability: Pathophysiology (Created in https://BioRender.com)
Over years of training and competition, these cyclically accelerated injuries could accelerate CTE progression. Instead of a slow, uniform decline, female athletes might experience cyclically accelerated neurodegeneration damage that peaks in menstrual cycle windows.
Understanding this relationship means the timing of impacts could matter as much as the frequency.
A Sex-Specific Solution: Timed Prophylactic Interventions
To address the cyclical vulnerability, a tri-mechanism therapy is proposed as a proactive approach to temporarily restore baseline hormonal neuroprotection lost and stabilise brain metabolism before high-impact events.
This strategy does not aim to cure traumatic brain injury (TBI, but to reinforce the brain’s natural defences during its most vulnerable phase.
Pathway 1: 17β-estradiol () – The Regulator
Estrogen acts like a cellular shield and regulates the calcium buffer. It enhances the removal of damaging free radicals, reactive oxygen species (ROS) and enhances calcium transfer pumps (PMCA/NCX), which actively remove calcium from the cell [8]. This boosts glutamate reuptake, reduces calcium entry and oxidative stress [9], [10].
Pathway 2: Progesterone – The Brake Pedal
Progesterone is metabolised into Allopregnanolone (ALLO), which then acts on GABA receptors (ligand-gated ion channels). ALLO assists GABA signals, making the brain brake more efficiently, reducing excitatory drive and creating a high threshold for excitotoxicity [11].
Pathway 3: Ketone (β-hydroxybutyrate): The Metabolic Fuel
Ketones provide an alternative fuel that bypasses damage [12]. They directly fuel the calcium extrusion pumps, helping the cell recover from stress. Ketones also increase GABA synthesis and enhance mitochondrial efficiency, which naturally lowers ROS production, providing cellular energy for the cell [13].
Together, these three pathways restore ROS balance, stabilise calcium hemostasis, and boost inhibitory signals (GABA), key defences against phase-specific neural vulnerability [14].
Figure 3: Pathways for Tri-mechanism Neuronal Protection During the Late Luteal Phase (Created in https://BioRender.com)
How to Implement: Timing is Everything
For the therapy to work, the interventions must be precisely timed to the late luteal phase (typically days 25-28), when estrogen and progesterone decline. This requires cycle tracking and individualised monitoring.
-
17β-estradiol (transdermal for bioavailability)
-
Micronised progesterone (oral or virginal)
-
Ketone supplement (beta-hydroxybutyrate, ketone esters, or MCT oil)
Temporarily restoring the brain’s hormonal baseline and metabolic stability during this may help female athletes minimise the cyclical vulnerability to head injury
Conclusion
Female athletes experience repeated impacts during the period of hormonal vulnerability, particularly the late luteal phase. This cyclical susceptibility may accelerate CTE progression, leading to episodic rather than steady neurodegeneration.
Times, sex specific timed preventative interventions combining a ketone supplement with hormone replacement therapy could restore neuroprotection and provide metabolic support during this window. For women in contact sports, such strategies could make the difference between ongoing neurodegeneration and sustained cognitive stability.
References
[1] K. Legerlotz and T. Nobis, “Insights in the Effect of Fluctuating Female Hormones on Injury Risk—Challenge and Chance,” Front Physiol, vol. 13, p. 827726, Feb. 2022, doi: 10.3389/fphys.2022.827726.
[2] N. K. McGroarty, S. M. Brown, and M. K. Mulcahey, “Sport-Related Concussion in Female Athletes: A Systematic Review,” Orthop J Sports Med, vol. 8, no. 7, p. 2325967120932306, July 2020, doi: 10.1177/2325967120932306.
[3] T. Covassin and R. J. Elbin, “The Female Athlete: The Role of Gender in the Assessment and Management of Sport-Related Concussion,” Clinics in Sports Medicine, vol. 30, no. 1, pp. 125–131, Jan. 2011, doi: 10.1016/j.csm.2010.08.001.
[4] M. Singh and C. Su, “Progesterone-induced neuroprotection: Factors that may predict therapeutic efficacy,” Brain Research, vol. 1514, pp. 98–106, June 2013, doi: 10.1016/j.brainres.2013.01.027.
[5] D. G. Stein, “Progesterone in the treatment of acute traumatic brain injury: a clinical perspective and update,” Neuroscience, vol. 191, pp. 101–106, Sept. 2011, doi: 10.1016/j.neuroscience.2011.04.013.
[6] Y.-J. Cheng, C.-H. Lin, and H.-Y. Lane, “From Menopause to Neurodegeneration—Molecular Basis and Potential Therapy,” Int J Mol Sci, vol. 22, no. 16, p. 8654, Aug. 2021, doi: 10.3390/ijms22168654.
[7] N. Graham et al., “Retired contact sports athletes with cognitive concerns: promoting lifelong brain health,” Practical Neurology, Oct. 2025, doi: 10.1136/pn-2025-004786.
[8] J. Nilsen and R. D. Brinton, “Mechanism of estrogen-mediated neuroprotection: Regulation of mitochondrial calcium and Bcl-2 expression,” Proc. Natl. Acad. Sci. U.S.A., vol. 100, no. 5, pp. 2842–2847, Mar. 2003, doi: 10.1073/pnas.0438041100.
[9] Ibrahim Khan, Kamran Saeed, Min Gi Jo, and Myeong Ok Kim, “17-β Estradiol Rescued Immature Rat Brain against Glutamate-Induced Oxidative Stress and Neurodegeneration via Regulating Nrf2/HO-1 and MAP-Kinase Signaling Pathway - PMC.” Accessed: Nov. 08, 2025. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC8229583/
[10] J. Lu, T.-J. Xian, C.-J. Li, and Y. Wang, “The estrogen–brain interface in neuroinflammation: a multidimensional mechanistic insight,” Front Aging Neurosci, vol. 17, p. 1671552, Sept. 2025, doi: 10.3389/fnagi.2025.1671552.
[11] Todd A Verdoorn, Tom J Parry, Graziano Pinna, and Jonathan Lifshitz, “Neurosteroid Receptor Modulators for Treating Traumatic Brain Injury.” Accessed: Nov. 08, 2025. [Online]. Available: https://pmc.ncbi.nlm.nih.gov/articles/PMC10684848/
[12] S. C. Cunnane et al., “Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer’s disease,” Annals of the New York Academy of Sciences, vol. 1367, no. 1, pp. 12–20, 2016, doi: 10.1111/nyas.12999.
[13] H. Yang, W. Shan, F. Zhu, J. Wu, and Q. Wang, “Ketone Bodies in Neurological Diseases: Focus on Neuroprotection and Underlying Mechanisms,” Front. Neurol., vol. 10, June 2019, doi: 10.3389/fneur.2019.00585.
[14] M. M, S. Pg, D. L, K. Dy, and R. Jm, “Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation,” Neuroscience, vol. 145, no. 1, Mar. 2007, doi: 10.1016/j.neuroscience.2006.11.065.
Add comment
Comments
I got drawn in by the title and stayed for the information - in my opinion it's a nicely structured blog which makes it easy for the reader to follow along as new points are brought forward. The use of a figure might've improved the understanding further - for example showing a graph with the fluctuating hormone levels throughout the month and red marks of where an injury would reap even worse health outcomes.
Thanks Paula! I've made the changes, hopefully it makes for a better read.
This was a really interesting read as I felt it contrasted how I looked upon the effects of oestrogen and CTE. To me I thought women had an advantage because they have naturally occuring oestrogen at a much higher concentration then men which made me think it was an advantage but i neglected to consider how the fluctuation of hormones during the menstrual cycle could affect this. Very interesting!
Thanks, Eimear! I was also under the same impression that oestrogen would provide neuroprotection for females in contact sports, and that was the angle I wanted to work on initially, if this neuroprotection in females could be transferred to men. When I started reading up on sex differences in TBI and Concussion amongst athletes, it clearly changed the trajectory of my blog.
Very interesting article! Similar to Eimear, I initially assumed that the anti-inflammatory effects of the hormones you mentioned would serve as another layer of protection from CTE, but if they are masking injury it opens the door for additional damage and subsequent significantly worse effects when hormone levels drop.
Thanks Stephen! There is still much more to explore regarding female hormones and CTE, and many important questions have not yet been properly addressed.
Nice read! Cool way to manage the vulnerability during the hormonal drop phase and to take advantage of the protective female hormones. But I had a couple of thoughts/questions while reading the article.
This theraputic solution suggested is meant to be used before high impact events, I think then that will be if they are expected to happen during the luteal phase or before menstruation, but isnt CTE the result of chronic impact happening over a long time rather than a specific acute one? especially that no one can predict a big accidental impact happening during training for example, or are you sugesting that reducing the most big impacts is already enough?
Another point is, how do you compare the use of birth contol solutions to your suggested method? I guess they dont offer as strong of a peak but they are easy to control long term and would provide some net for all days especially the really low progesterone ones.
This method might actually even benefit from a special made tracker because everytime the triple solution is used the menstruation is delyed by few days making a constant shift in tracking important for this to succeed.
Then there´s also the potential impact of delaying the menstruation on the severity of it leadin to possible reduced performance or missing training days.
A lot to think about! Women athletes are really on another level having to put their bodies through extreme limits even on days where hormones are working aginst them!
Another interesting article regarding this topic: https://www.bbc.com/sport/68631176
Thanks Deena! I believe I've answered most of your questions in another comment. The reason I didn't go the contraceptive route is because they've already been studies on it.
I'll check out the blog, thanks.
This was a fascinating read — I had never really thought about the idea that the “risk window” for brain injury in women could fluctuate so dramatically across a single month. The way you explained the late luteal phase as a period of dual hormone withdrawal made it so clear why the brain might be more exposed at that point, especially with the estrogen/ALLO drop happening at the same time.
I’m really interested in the preventative approach you suggested, but it made me wonder about the long-term practical side of it. Since CTE develops from years of repeated hits rather than isolated events, do you think targeting only the most vulnerable days would be enough to make a meaningful difference over an athlete’s whole career? Or could it end up being something that needs to be used almost every cycle for years on end?
I’m also curious about how this compares to hormonal contraceptives, because they flatten the cycle quite a bit — could that theoretically reduce this vulnerability window, or would the lack of natural hormone peaks bring its own risks?
Either way, this definitely opened my eyes to how much female athletes have to manage behind the scenes that male athletes never even think about.
Thanks, Grace! To clarify, the proposed interventions are meant to reduce vulnerability during the luteal phase, not to make the female brain “more protected” overall compared to males. But if the hypothesis is correct, and impacts during the luteal phase are disproportionately harmful,then targeting those 3–4 vulnerable days per month could meaningfully reduce cumulative risk. For example, if 50 baseline impacts are equivalent to lets say 5 impacts during the luteal period, then mitigating exposure during that window could make a substantial difference over a career.
I haven’t fully thought through the ideal dose or duration of interventions yet. It’s possible that taking it continuously throughout an athlete’s career might help, but it’s far from certain.
Regarding contraceptives, one study found that female athletes who were not on hormonal contraception at the time of injury experienced worse symptoms compared with those who were (Study: Preliminary Evidence for a Window of Increased Vulnerability to Sustain a Concussion in Females: A Brief Report). However, the study had limitations like small sample size and self-reporting, so it shouldn’t be overinterpreted.
My more comprehensive approach is for female athletes to integrate menstrual cycle phase into training and recovery planning. For example, high-risk activities could be minimized during ovulation, when hormonal fluctuations might elevate vulnerability to TBI. Similarly, recovery strategies could be optimized during phases when the body is better primed for repair. In the most conservative scenario, athletes could even sit out games during the luteal phase, although the athletes I’ve talked to weren’t particularly keen about that idea.
Great read and a very interesting read. I liked how you clearly gave treatment options and the method of administration for each medication.
Thanks Baneen!