Introduction
Imagine being a retired professional rugby player and realising you can’t remember the career you have left behind. This is exactly what famous French international Sébastien Chabal said in a recent interview [1]. It’s a worrying statement for world rugby to hear, but it does ask the question of how these repeated head impacts experienced in sports like rugby affect the brain over time. There is a lot of evidence linking repeated head injuries to chronic traumatic encephalopathy (CTE), making stories like Chabal’s particularly concerning [2]. CTE is a brain condition heavily linked to repeated head trauma in which nerve cells gradually become damaged and die. Symptoms such as memory loss, mood changes, and concentration issues often appear years or even decades after the injuries, allowing the disease to progress unnoticed. By the time these symptoms show up, the damage is often already advanced, and to make things worse, CTE can only be definitively diagnosed after death during a post-mortem examination of brain tissue [3,4].
How it happens - The Biochemistry
Repeated impacts to the head trigger complex changes in the brain. Tau proteins become abnormally phosphorylated, causing them to clump together into tangles that disrupt neuron function [5]. TDP43 is another protein that peaks 3-7 days after injury accumulating in the microglia and astrocytes, the brains immune and support cells and this keeps them in a state associated with inflammation [6]. In this state they release molecules to clear debris and damaged cells. However, repeated injuries prevent the brain from switching to a state associated with anti-inflammatory characteristics. The prolonged pro-inflammatory environment gradually impairs brain function and over time it is this ongoing inflammation that contributes to a person developing CTE and neurodegenerative diseases.
Why Sex might contribute:
We know that women are more prone to concussions, yet most reported cases of CTE have been in males, leaving many questions as to why. One factor is exposure, although women face a higher concussion risk, men are more often involved in high-contact sports like rugby and the NFL. Sampling bias may also play a role, as most CTE research has examined the brains of former male athletes, who make up most donations to research[7]. While these findings are promising, they may still be skewed, as they rarely account for biological differences between males and females. This is where hormonal differences become interesting. Oestradiol, a potent form of the female hormone Oestrogen, influences many biological functions, including dampening neuroinflammation after brain injury. So, could oestrogen help reduce inflammation before CTE develops?
Role of the Microglia
Macrophages are the white blood cells of the immune system that engulf and digest pathogens. Microglia are the brains resident immune cells that work hard to clear plaques and damaged neurons but when this becomes overactive it can have a devastating effect on the brain.[8] The spectrum of microglial differentiation provides a framework for exploring how biological modifiers, including hormones, shape post-injury inflammation [9].
Figure 1: Microglial response to Single Head Injuries vs Repeated Head Injuries.
The role of Oestradiol:
Oestradiol is a form of oestrogen which can also be referred to as E2. It plays a role in many different biological functions including memory. An important function of oestradiol in this context is its ability to influence microglia to differentiate to repair associated states and dampen neuroinflammation.
Although this has not yet been considered in relation to CTE.[10]
Figure 2: Microglia activation by estradiol post brain injury
Therapeutic Options:
Previous CTE research has focused on male rats and mice, reflecting the higher prevalence of head injuries in men. However, emerging studies suggest hormone replacement therapy (HRT) could offer protection. 17β-oestradiol promotes repair-associated microglial states (M2), potentially countering the pro-inflammatory pathways implicated in CTE. Females naturally have around ten times more oestrogen than males [11], which may partly explain the apparent male predominance of CTE
Things to consider:
Multiple variables should be considered. Hormone dose in males is critical, as high concentrations could disrupt hormonal balance and cause secondary sexual characteristics. Receptor selectivity may also vary between individuals. Trials could include participants of different ages, sexes, and backgrounds, though this may be challenging since most CTE patients are male athletes.
Study design:
Many previous therapeutic studies in TBIs and CTE have used male rats and mice, often using controlled cortical impact (CCI) to generate CTE-like pathology. These models are good at producing CTE features, but not many studies have examined females, despite evidence that women may be more susceptible to sports-related concussions [12]. This raises a key question: if women are more prone to concussions, why do men show higher CTE prevalence? We propose that higher levels of 17β-estradiol in females, which promote repair-associated (M2) microglial states, could enhance recovery from TBIs and reduce CTE development. To test this, a study comparing female and male rats using CCI could determine whether females show reduced pathology. If so, isolating and administering 17β-estradiol to males may represent a promising therapeutic approach.
Conclusion:
Stories like Sébastien Chabal’s remind us how repeated head impacts in sports like rugby can quietly affect the brain, sometimes leading to CTE. While most diagnosed cases have been in men, this doesn’t tell the whole story, differences in exposure, sampling, and biological sex likely play a role. Oestradiol, found at higher levels in females, may help dampen neuroinflammation and promote recovery after injury. Studying how hormones influence microglial responses could explain these sex differences and offer new therapeutic strategies. Understanding these mechanisms is a crucial step toward protecting all athletes from long-term brain injury.
References:
- Sky Sports. Sébastien Chabal reveals he cannot remember a single second of rugby due to amnesia [Internet]. Sky Sports; 2025 [cited 27 Sep 2025]. Available from: https://www.skysports.com/rugby-union/news/12321/13346399/sebastien-chabal-
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- Byard R, Tiemensma M, Buckland ME, Vink R. Chronic traumatic encephalopathy (CTE) – features and forensic considerations. Forensic Sci Med Pathol. 2023 Dec;19(4):620–624. doi:
10.1007/s12024-023-00624-3. Epub 2023 Apr 14. PMID: 37058211; PMCID: PMC10752833. [cited 28 Sept 2025].
- Rawlings S, Takechi R, Lavender AP. Effects of sub-concussion on neuropsychological performance and its potential mechanisms: A narrative review. Brain Res Bull. 2020
Dec;165:56-62. doi: 10.1016/j.brainresbull.2020.09.021. Epub 2020 Oct 1. PMID: 33011196. [cited 03 Oct 2025]
- Mayo Clinic. Chronic traumatic encephalopathy (CTE) [Internet]. Mayo Clinic; 2023 [cited 2025 Oct 10]. Available from: https://www.mayoclinic.org/diseasesconditions/chronictraumatic-encephalopathy. [accessed 03 Oct 2025]
- McKee AC, Stein TD, Huber BR, Crary JF, Bieniek K, Dickson D, Alvarez VE, Cherry JD, Farrell K, Butler M, Uretsky M, Abdolmohammadi B, Alosco ML, Tripodis Y, Mez J, Daneshvar DH. Chronic traumatic encephalopathy (CTE): criteria for neuropathological diagnosis and relationship to repetitive head impacts. Acta Neuropathol. 2023 Apr;145(4):371-394. doi: 10.1007/s00401-023-02540-w. Epub 2023 Feb 10. PMID: 36759368; PMCID: PMC10020327.
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Sirko S, Günes ZI, Liebscher S, Schlegel J, Aliee H, Theis F, Meiners S, Kiebler M, Dormann D, Ninkovic J. TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury. Nat Neurosci. 2022 Dec;25(12):1608-1625. doi:
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- Wu H, Zheng J, Xu S, Fang Y, Wu Y, Zeng J, Shao A, Shi L, Lu J, Mei S, Wang X, Guo X, Wang Y, Zhao Z, Zhang J. Mer regulates microglial/macrophage M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury. J Neuroinflammation. 2021 Jan
5;18(1):2. doi: 10.1186/s12974-020-02041-7. PMID: 33402181; PMCID: PMC7787000. Mer regulates microglial/macrophage M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury - PubMed
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10.3389/fragi.2023.1231706. PMID: 37744008; PMCID: PMC10513083. The dual face of microglia (M1/M2) as a potential target in the protective effect of nutraceuticals against neurodegenerative diseases - PubMed
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Comments
Great post! I found the role of oestrogen in preventing CTE development in women very interesting and was wondering if birth control that contains oestrogen could possibly provide any form of protection in young female athletes against CTE?
Thanks Emma! The idea behind putting more research into female athletes was to see whether the higher concentration of oestrogen in females could contribute to the lower numbers of CTE recorded in females. Birth control could potentially contribute to this but our idea is to see if we were to give males oestrogen would the numbers of CTE recorded be as less as women. This way we could see if oestrogen contributes.
This was very interesting to read! It is fascinating to see how hormones are playing different roles for both genders in the development of CTE. It would be interesting to see what studies would conclude if they used female mice or rats using Emma's idea!