The Level of Salivary Testosterone and Pain Perception Show Sex-Specific Associations in Healthy Adults, But Not in Migraine Patients

Introduction

Understanding the complexity of pain and the role gender plays in pain perception is of significant importance in medical research. Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, influenced by various intrinsic and extrinsic factors such as genetics, emotional state, and gender differences. Specifically, there is extensive research indicating that testosterone is associated with pain relief. However, the specific role of gender in these associations remains largely unknown. This has driven researchers to explore the association between salivary testosterone levels and pain perception in healthy adults and migraine patients.

Research Background and Objective

The authors of this paper focused on the gender-specific association between salivary testosterone and pain perception, selecting migraine as the research subject since it is a common pain disorder with a global prevalence of about 15%. The objective of the study is to explore whether there is a gender-specific association between salivary testosterone levels and pain perception in healthy individuals and migraine patients, and whether migraine disrupts this association.

Research Source

This paper was written by researchers including Li-Ling Hope Pan and Shih-Pin Chen from National Yang Ming Chiao Tung University and was published in the 2024 issue of The Journal of Pain. The research team includes researchers from Taipei Veterans General Hospital, Sapienza University of Rome Polo Pontino, and Heidelberg University among other institutions.

Research Methods

Participants

The study recruited 88 healthy controls (HCs) and 75 migraine patients (MIG) aged between 20 and 50 years from September 2019 to May 2023. Healthy controls had to meet criteria such as no major systemic diseases, no neural disorders, and no history of mental illnesses. The migraine group needed to meet the migraine diagnosis criteria of the third edition of the International Classification of Headache Disorders (ICHD-3) and had not received preventive treatment for migraines for at least 3 months.

Experimental Procedures

1. Questionnaire Assessment: Participants filled out a series of questionnaires including the Pittsburgh Sleep Quality Index, Perceived Stress Scale, Hospital Anxiety and Depression Scale, and Pain Sensitivity Questionnaire to evaluate psychological and psychosocial states.
2. Saliva Sampling: Salivary testosterone levels were measured using a commercial ELISA kit. Samples were collected between 9 AM and 3 PM to reduce diurnal variation.
3. Pain Perception Evaluation: Heat pain thresholds (HPT) and 45°C pain perception scores (PPS) were assessed using the Medoc TSA-II neuro-sensory analyzer. Each assessment was repeated five times, and the average was taken.

Data Analysis

Various statistical methods were used, including one-way and two-way ANOVAs, Pearson correlation analysis, and linear regression models. Significance was set at p < .05.

Main Results

Healthy Control Group

• Testosterone Levels: Male controls had significantly higher testosterone levels than females (142.1 ± 40.8 vs. 74.3 ± 42.6 pg/ml).
• Correlation: Male controls showed a significant positive correlation between testosterone levels and PPS (r = .341, p = .029), whereas females showed a significant negative correlation (r = −.407, p = .005).
• Controlled Variable Analysis: The correlations remained consistent when considering BMI and evaluation time.

Migraine Group

• Testosterone Levels: Male migraine patients had significantly higher testosterone levels than females (157.1 ± 45.7 vs. 87.8 ± 48.1 pg/ml).
• Correlation Failure: No significant correlation between testosterone levels and PPS was found in the migraine group regardless of gender. This may be due to the disruption of the testosterone-pain perception association by frequent headache attacks in migraine patients.

Self-Reported Pain Sensitivity

• No Significant Gender Differences: There were no significant gender differences in the self-reported pain sensitivity questionnaire results for both healthy controls and migraine groups.

Menstrual Cycle Influence

• Menstrual Period Analysis: There was no significant difference in salivary testosterone levels during the menstrual period for female participants. The correlation between testosterone levels and PPS remained significant after controlling for the menstrual period (HC: r = −.381, n = 47, p = .009; MIG: r = −.022, n = 45, p = .885).

Discussion

The study results indicate that there is a gender-specific, opposite association between salivary testosterone levels and pain perception in healthy men and women. However, this association is absent in migraine patients. Elevated testosterone levels were associated with higher pain scores in healthy male controls but had protective effects in healthy female controls, illustrating different pain processing mechanisms in different genders.

Reasons for Gender Differences

• Potential Causes of Gender Differences: This might be due to the different roles of gender in immune system regulation. Men rely more on microglia-mediated pain, while women rely more on T-cells.
• Role of the Endocannabinoid System: The endocannabinoid system is known to inhibit testosterone release, which in turn affects the endogenous analgesia capability.

Clinical Significance and Future Prospects

• Clinical Relevance of Supra-threshold Pain: Clinically, various pains such as migraines and back pain often manifest as supra-threshold pain. Studying supra-threshold pain perception scores can provide more information about pain processing.
• Brain Network Changes: Previous studies have shown intrinsic alterations in the default mode network and salience network in patients with pain conditions, and studying supra-threshold pain will further elucidate this area.

Limitations

This study’s limitations include not including other sex hormones, not considering racial and age differences, small sample size, inconsistencies in saliva sampling time, and the menstrual period estimation method. Future research should aim to verify these findings across more diverse racial and age ranges and further elucidate the mechanisms of gender differences in testosterone and pain perception.

Conclusion

The study results indicate that there is a significant gender-specific association between salivary testosterone levels and pain perception in healthy men and women, but this relationship is disrupted in migraine patients. This research provides a new perspective for understanding the relationship between sex hormones and pain perception, contributing to future pain management and gender medicine research.