How do hormones impact muscle function in FSHD?

By Dr. Lucienne Ronco

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This is a question we often hear from FSHD patients. Human hormones, like estrogen, impact muscle health in general, not just in disease. In healthy muscle, they support muscle function and growth. This conversation intensified after a new paper by Dr. Silvia Maiullari found that estrogen might counteract DUX4 activity in an FSHD mouse model with human disease characteristics (Maiullari et al., 2025). While this is an interesting finding, there is much work to do. Key questions include: How much estrogen is needed to block DUX4 activity? Does estrogen work at all stages of muscle function and FSHD progression? Does this happen in human disease?

This recent finding suggests a role for estrogen in FSHD and that doctors might see a difference between males and females in disease characteristics. But there is no simple relationship between sex and the course of FSHD over a person’s lifetime. For example, in the general FSHD population, a greater proportion of genetically confirmed females tend to remain asymptomatic. Consistent with this, by age 30, males are generally more severely affected than females, but women may be more likely to progress to wheelchair use than men. In a 2024 presentation at MDA, however, a comprehensive analysis done by Dr. Natalie Katz of the US National Registry, revealed sex-based disparities in early-onset FSHD, showing that girls are diagnosed at a significantly younger age than boys and experience more severe outcomes. From all of these findings together, we recognize a complex relationship between biological sex and FSHD. In females, estrogen levels rise through puberty and fall after menopause, and this may partially explain the difference in disease progression in early-onset girls vs women assessed over their lifetime.

A study by Dr. Karlien Mul in 2018 asked whether a relationship between lifetime estrogen exposure and disease severity in FSHD patients existed. They found no correlation between estrogen exposure and disease severity, suggesting small variations in estrogen exposure over a woman’s lifetime might not be enough to significantly impact disease progression. Also, hormonal changes during menopause did not have substantial impacts on disease trajectory. In fact, women often reported mixed experiences regarding disease progression during hormonal changes, with both accelerations and decelerations.

Flavonoids are a type of bioactive phytochemical found in plants that can mimic some estrogen activities and have possible medicinal properties. Because of these properties, flavonoids have been tested in human FSHD trials and were reviewed in 2021 (Hangul, et al., 2021). Four studies were conducted and found minimal positive effects; however, they were small studies and more work could be done in larger groups of FSHD patients.

Taken together, the studies clearly suggest a role for estrogen in skeletal muscle and FSHD. More research is needed to explore the exact impacts of hormones and hormone-related molecules in order to fully understand their role and relationship of age and hormone levels to FSHD.

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References

Maiullari, S., et al. (2025). Estrogen rescues muscle regeneration impaired by DUX4 in a humanized xenograft mouse model. Cell Death & Disease. https://doi.org/10.1038/s41419-025-07827-2

Mul, K., Horlings, C. G. C., Voermans, N. C., Schreuder, T. H. A., & van Engelen, B. G. M. (2018). Lifetime endogenous estrogen exposure and disease severity in women with facioscapulohumeral muscular dystrophy. Neuromuscular Disorders, 28(6), 508–511. https://doi.org/10.1016/j.nmd.2018.03.006

Hangül, C., et al. (2021). Promising Perspective to Facioscapulohumeral Muscular Dystrophy Treatment: Nutraceuticals and Phytochemicals. Current Neuropharmacology. https://doi.org/10.2174/1570159X19666210726151924

Katz, N. (2024, March 6). US National Registry Analysis Reveals Gender Disparities in Pediatric-Onset Facioscapulohumeral Muscular Dystrophy. Muscular Dystrophy Association (MDA) Clinical & Scientific Conference. https://www.neurologylive.com/view/us-national-registry-analysis-reveals-gender-disparities-pediatric-onset-fshd