Background & Aims

Mounting evidence has revealed sex-specific differences in chronic pain conditions, such as migraines [1], as well as in the mechanisms of pain processing and modulation. The balance and the levels of testosterone and estrogen were reported to affect one’s perception of pain. [2] However, the sex differences in the association between gonadal hormones and pain perception remain to be explored, particularly in healthy individuals. Moreover, continual pain conditions are thought to interfere with pain processing. [3, 4] Therefore, this exploratory study investigated the association between pain perception and salivary testosterone levels in both healthy controls (HCs) and patients with migraines (MIGs). We hypothesized that discernible sex differences would be identified in the association between experimental pain levels and testosterone levels, and that this relationship may be further complicated in MIG.

Methods

Male and female HCs without any pain conditions and MIGs who received a migraine diagnosis based on the International Classification of Headache Disorders, 3rd Edition (ICHD-3)[5] were recruited. The participants sequentially finished a questionnaire battery, saliva sample collection, and pain assessments. The participants completed a series of questionnaires to evaluate their psychosocial profiles, including mood, stress, and sleep quality data. Saliva samples were collected using Salivette Cortisol commercial collection tubes (Sarstedt, Germany), and salivary testosterone levels were analyzed using a commercial enzyme-linked immunosorbent assay kit (Salimetrics 1-2402, Testosterone ELISA Kit). Heat pain thresholds and suprathreshold pain ratings at 45°C (referred to as the pain perception score, PPS) were assessed using Medoc TSA-II NeuroSensory Analyzer (Medoc, Israel). A 30 mm × 30 mm Thermode probe was securely placed on the left ventromedial forearm.

Results

A total of 88 HCs (men: 41, age: 29.9±7.7 years) and 75 MIGs (men: 30, age: 31.1±7.7 years) completed all assessments. A positive correlation between testosterone levels and PPS was identified in the male HCs (r=0.341, P=0.029), whereas a negative correlation was identified in the female HCs (r=?0.407, P=0.005). No such correlations were identified in the MIG group. Subanalysis to control for the menstrual phase and noted no significant differences in testosterone levels between women in the ovulation (n = 17) and nonovulation phases (n = 75; P = 0.912, Mann–Whitney U test). To improve the robustness of our results, we performed a partial correlation analysis between PPS and testosterone levels, controlling for the menstrual phase, and obtained similar results (HC: r = ?0.381, P = 0.009; MIG: r = ?0.034, P = 0.829). The comparison was made between HC and MIG in males and females, respectively. No significant differences were found between groups in both sexes.

Conclusions

This study confirms that a negative relationship is present between PPS and testosterone levels in female HCs, which is in line with the findings of studies that have considered testosterone to be an antinociceptive agent. Our study is the first to demonstrate a sex-specific association between PPS and testosterone levels in HCs. Moreover, this study also revealed that the presence of a chronic pain condition, such as migraine, appears to disrupt this association.

References

1. Stovner LJ, Hagen K, Linde M, Steiner TJ (2022) The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. J Headache Pain 23:34. https://doi.org/10.1186/s10194-022-01402-2
2. Vincent K, Tracey I (2008) Hormones and their Interaction with the Pain Experience. Rev Pain 2:20. https://doi.org/10.1177/204946370800200206
3. Baliki MN, Geha PY, Apkarian AV, Chialvo DR (2008) Beyond Feeling: Chronic Pain Hurts the Brain, Disrupting the Default-Mode Network Dynamics. J Neurosci 28:1398–1403. https://doi.org/10.1523/JNEUROSCI.4123-07.2008
4. Mano H, Seymour B (2015) Pain: A Distributed Brain Information Network? PLoS Biol 13:e1002037. https://doi.org/10.1371/journal.pbio.1002037
5. Headache Classification Committee of the International Headache Society (2018) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 38:1–211. https://doi.org/10.1177/0333102417738202

Presenting Author

Li-Ling Hope Pan

Poster Authors

Li-Ling Hope Pan, PhD

PT, Ph.D.

Brain Research Center, National Yang Ming Chiao Tung University

Lead Author

Shih-Pin Chen

MD

Institute of Clinical Medicine, National Yang Ming Chiao Tung University

Lead Author

Yu-Hsiang Ling

MD

College of Medicine, National Yang Ming Chiao Tung University

Lead Author

Yen-Feng Wang

MD

Department of Neurology, Neurological Institute, Taipei Veterans General Hospital

Lead Author

Kuan-Lin Lai

MD

Department of Neurology, Neurological Institute, Taipei Veterans General Hospital

Lead Author

Hung-Yu Liu

Department of Neurology, Neurological Institute, Taipei Veterans General Hospital

Lead Author

Wei-Ta Chen

MD

Department of Neurology, Keelung Hospital, Ministry of Health and Welfare

Lead Author

William Huang

MD

Department of Urology, Taipei Veterans General Hospital

Lead Author

Gianluca Coppola

MD

Department of Medico?Surgical Sciences and Biotechnologies, Sapienza University of Rome Polo Pont

Lead Author

Rolf-Detlef Treede

Heidelberg University

Lead Author

Shuu-Jiun Wang

PhD

College of Medicine, National Yang Ming Chiao Tung University

Lead Author

Topics

  • Mechanisms: Biological-Systems (Physiology/Anatomy)