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Objective Androgens have been hypothesized to be involved in the pathophysiology of cluster headache due to the male predominance, but whether androgens are altered in patients with cluster headache remains unclear. Methods We performed a prospective, case-controlled study in adult males with cluster headache. Sera were measured for hormones including testosterone, luteinizing hormone (LH), and sex hormone-binding globulin in 60 participants with episodic cluster headache (during a bout and in remission), 60 participants with chronic cluster headache, and 60 age- and sex-matched healthy controls. Free testosterone (fT) was calculated according to the Vermeulen equation. Shared genetic risk variants were assessed between cluster headache and testosterone concentrations. Results The mean fT/LH ratio was reduced by 35% (95% confidence interval [CI]: 21%–47%, p < 0.0001) in patients with chronic cluster headache and by 24% (95% CI: 9%–37%, p = 0.004) in patients with episodic cluster headache compared to controls after adjusting for age, sleep duration, and use of acute medication. Androgen concentrations did not differ between bouts and remissions. Furthermore, a shared genetic risk allele, rs112572874 (located in the intron of the microtubule associated protein tau (MAPT) gene on chromosome 17), between fT and cluster headache was identified. Interpretation Our results demonstrate that the male endocrine system is altered in patients with cluster headache to a state of compensated hypogonadism, and this is not an epiphenomenon associated with sleep or the use of acute medication. Together with the identified shared genetic risk allele, this may suggest a pathophysiological link between cluster headache and fT. ANN NEUROL 2024, Objective: Androgens have been hypothesized to be involved in the pathophysiology of cluster headache due to the male predominance, but whether androgens are altered in patients with cluster headache remains unclear. Methods: We performed a prospective, case-controlled study in adult males with cluster headache. Sera were measured for hormones including testosterone, luteinizing hormone (LH), and sex hormone-binding globulin in 60 participants with episodic cluster headache (during a bout and in remission), 60 participants with chronic cluster headache, and 60 age- and sex-matched healthy controls. Free testosterone (fT) was calculated according to the Vermeulen equation. Shared genetic risk variants were assessed between cluster headache and testosterone concentrations. Results: The mean fT/LH ratio was reduced by 35% (95% confidence interval [CI]: 21%–47%, p < 0.0001) in patients with chronic cluster headache and by 24% (95% CI: 9%–37%, p = 0.004) in patients with episodic cluster headache compared to controls after adjusting for age, sleep duration, and use of acute medication. Androgen concentrations did not differ between bouts and remissions. Furthermore, a shared genetic risk allele, rs112572874 (located in the intron of the microtubule associated protein tau (MAPT) gene on chromosome 17), between fT and cluster headache was identified. Interpretation: Our results demonstrate that the male endocrine system is altered in patients with cluster headache to a state of compensated hypogonadism, and this is not an epiphenomenon associated with sleep or the use of acute medication. Together with the identified shared genetic risk allele, this may suggest a pathophysiological link between cluster headache and fT. ANN NEUROL 2024.

Objective To systematically investigate previously examined biomarkers in blood, urine, cerebrospinal fluid, tear fluid, and saliva of patients with cluster headache. Background Cluster headache is a condition with extensive clinical challenges in terms of diagnosis and treatment. Identification of a biomarker with diagnostic implications or as a potential treatment target is highly warranted. Methods We conducted a systematic review including peer reviewed full text of studies that measured biochemical compounds in either blood, urine, cerebrospinal fluid, tear fluid, or saliva of patients with cluster headache diagnosed after the implementation of the International Classification of Headache Disorders (1988) written in English, Danish, Swedish, or Norwegian. Inclusion required a minimum of five participants. The search was conducted in PubMed and EMBASE, in September 2022, and extracted data were screened by two authors. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting systematic reviews were followed. The Newcastle–Ottawa Scale was used to assess the risk of bias in case–controlled studies. Results We included 40 studies involving 832 patients with cluster headache and 872 controls, evaluating 80 potential biomarkers. The risk of bias for case–controlled studies was a median of 6 (range: 3–8) and 20 studies out of 40 (50%) were of fair or good quality. Most studies were identified within three groups: hypothalamic-regulated hormones, inflammatory markers, and neuropeptides. Among the hypothalamic hormones, cortisol was the most frequently investigated (N = 7) and was elevated in cluster headache in most of the studies. The most frequently examined inflammatory marker was interleukin 1 (N = 3), but findings were divergent. Calcitonin gene–related peptide was the most investigated neuropeptide (N = 9) and all studies found increased levels during attacks. Conclusion B, Objective: To systematically investigate previously examined biomarkers in blood, urine, cerebrospinal fluid, tear fluid, and saliva of patients with cluster headache. Background: Cluster headache is a condition with extensive clinical challenges in terms of diagnosis and treatment. Identification of a biomarker with diagnostic implications or as a potential treatment target is highly warranted. Methods: We conducted a systematic review including peer reviewed full text of studies that measured biochemical compounds in either blood, urine, cerebrospinal fluid, tear fluid, or saliva of patients with cluster headache diagnosed after the implementation of the International Classification of Headache Disorders (1988) written in English, Danish, Swedish, or Norwegian. Inclusion required a minimum of five participants. The search was conducted in PubMed and EMBASE, in September 2022, and extracted data were screened by two authors. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting systematic reviews were followed. The Newcastle–Ottawa Scale was used to assess the risk of bias in case–controlled studies. Results: We included 40 studies involving 832 patients with cluster headache and 872 controls, evaluating 80 potential biomarkers. The risk of bias for case–controlled studies was a median of 6 (range: 3–8) and 20 studies out of 40 (50%) were of fair or good quality. Most studies were identified within three groups: hypothalamic-regulated hormones, inflammatory markers, and neuropeptides. Among the hypothalamic hormones, cortisol was the most frequently investigated (N = 7) and was elevated in cluster headache in most of the studies. The most frequently examined inflammatory marker was interleukin 1 (N = 3), but findings were divergent. Calcitonin gene–related peptide was the most investigated neuropeptide (N = 9) and all studies found increased levels during attacks. Conclusion: Biomarker findings have been inconsistent and wid