Liquid Chromatography–Mass Spectrometry Profiling Reveals Distinct Steroid Hormone Signatures in Chronic and Episodic Cluster Headache

Cluster headache (CH) in men has been linked to changes in hormone production, particularly lower function of the testes despite normal hormone levels being maintained. Researchers still do not know whether hormone production by the adrenal glands is also affected or how this may contribute to cluster headaches. In a recent study, scientists examined hormone patterns in people with cluster headaches, comparing different stages of episodic cluster headache as well as chronic and episodic forms of the condition. Blood samples taken after fasting were analyzed using liquid chromatography–mass spectrometry (LC-MS) to measure 16 different steroid hormones, including stress hormones and sex hormones. Researchers also used machine learning techniques to see whether these hormone patterns could help distinguish between different types of cluster headache. A paper based on this work was published in The Journal of Headache and Pain.¹

What Is a Cluster Headache, and How Might Sex Hormones Be Involved in the Condition?

A severe type of headache disorder that causes intense pain around or behind one eye, CH is often described as one of the worst kinds of pain a person can experience. Attacks usually last between 15 minutes and three hours, can happen up to eight times a day, and are often accompanied by symptoms on the same side of the face, such as tearing, a runny nose, or restlessness. People who go for more than three months without attacks during a year are considered to have episodic cluster headache (ECH). Those currently experiencing attacks are described as “in bout” (ECHb), while those in a symptom-free period are called “in remission” (ECHr). People who do not have these longer symptom-free periods are classified as having chronic cluster headache (CCH).²

Cluster headache is much more common in men, with roughly three to four times as many males affected as females. This is the opposite of many other headache disorders, which tend to occur more often in women.³ This suggests that sex hormones may play a role in cluster headache. In fact, earlier research has found that men with cluster headache often have lower levels of free testosterone and signs of “compensated” hormone imbalance, where the body tries to maintain normal hormone function despite underlying disruption.⁴

How Do Hormone Levels Differ Between Chronic and Episodic Cluster Headache?

The study included three groups made up of 60 adult men each with chronic cluster headache, episodic cluster headache both during and between headache periods, and healthy volunteers, respectively. Researchers found that several hormone levels were lower in people with episodic cluster headache compared with healthy individuals. These hormone levels dropped even further during active headache periods compared with times when symptoms were absent.

Men with chronic cluster headache also showed reduced levels of certain hormones, along with a higher imbalance between stress hormones and other steroid hormones. Using these hormone patterns, researchers were able to accurately tell the difference between chronic and episodic cluster headache in many cases. The study also found that, in episodic cluster headache, hormone changes were linked to how often attacks occurred and how recently the last attack happened, although this pattern was not seen in chronic cluster headache.

What Do These Differences Suggest About the Biology of the Condition?

“Overall,” write the authors of the paper,¹ “our findings suggest that adrenal gland dysfunction may underlie the disrupted circulating steroid concentrations in cluster headache, rather than gonadal dysfunction. Clear differences were observed between the steroid phenotypes of CCH and ECHb. These alterations are, however, likely secondary to other factors, rather than causal drivers of cluster headache attacks. Our findings support the notion that CCH and ECH may have distinct neurobiological underpinnings, despite presenting with similar clinical phenotypes.”

The researchers say more studies are needed to better understand why these hormone changes occur and how they may contribute to the development and symptoms of cluster headaches.¹

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References

1. 1.Westgate, C. S. J.; Lylloff, T.; Kristensen D. M. et al. Adrenal Gland Dysfunction in Males with Cluster Headache. J Headache Pain 2026. DOI: 10.1186/s10194-026-02386-z
2. Petersen, A. S.; Lund, N.; Goadsby, P. J. et al. Recent Advances in Diagnosing, Managing, and Understanding the Pathophysiology of Cluster Headache. Lancet Neurol 2024, 23, 712–724. DOI: 10.1016/S1474-4422(24)00143-1
3. Fischera, M.; Marziniak, M.; Gralow, I.; Evers, S. The Incidence and Prevalence of Cluster Headache: A Meta-Analysis of Population-Based Studies. Cephalalgia 2008, 28, 614–618. DOI: 10.1111/j.1468-2982.2008.01592.x
4. 4.Petersen, A. S.; Kristensen, D. M.; Westgate, C. S. J. et al. Compensated Hypogonadism Identified in Males with Cluster Headache: A Prospective Case‐Controlled Study. Ann Neurol 2024, 95, 1149–1161. DOI: 10.1002/ana.26906