Puberty, Sex Hormones and Pain Sensitivity in Adolescents With Migraine (IHS)

Hormonal Effects of Puberty-Related Alterations on Pain in Adolescents With Migraine

The purpose of this research study is to investigate the relationships between sex hormone levels and experimental pain sensitivity and migraine severity will be examined.

Study Overview

• Status: Active, not recruiting
• Conditions: Migraine
• Intervention / Treatment: Device: Pressure stimuli; Behavioral: Pressure pain thresholds (PPT); Device: Thermal stimuli; Behavioral: Pain ratings; Behavioral: Conditioned pain modulation (CPM) response; Behavioral: PedMIDAS (Pediatric Migraine Disability Assessment); Diagnostic test: Hormonal assessment; Other: Pubertal status

Detailed Description

This study will investigate how puberty and variability in sex hormone levels impact pain sensitivity and migraine symptoms.

Hypothesis 1- A significant reduction in pain sensitivity from early to late pubertal status will be found only for adolescents without but not with migraine during pubertal maturation.

Hypothesis 2- Experimental pain sensitivity will be negatively correlated with testosterone levels in adolescents in both groups (with and without migraine).

Exploratory Hypothesis 1- In adolescents with migraine, higher migraine severity (headache frequency and migraine disability) will be associated with lower testosterone levels.

Exploratory hypothesis 2- Adolescents with migraine will have lower testosterone levels than those without.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 11 years to 15 years (Child)
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria

1. Age between 11-15
2. Males and females
3. English speakers
4. Migraine group: diagnosed with migraine
5. Control group: Healthy, with no first degree relative with migraine

Exclusion criteria:

1. Pregnancy or breastfeeding,
2. Chronic pain (except for migraine for the migraine group), neurological or psychiatric syndromes or syndromes associated with pubertal maturation
3. Use of medications that impact sex hormone levels (i.e., contraceptive pills)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Migraine; Adolescents with a migraine diagnosis	Device: Pressure stimuli; Pressure stimuli will be applied by using a handheld algometer (Wagner Instruments) or the Pressure Algometer (Medoc, Ramat Yishai, Israel). These devices have a round probe that allows quantifying the amount of pressure that is being applied. The Pressure Algometer allows a real-time visual feedback to control and monitor applied pressure rates. Pressure will be applied to the lower leg, volar forearm, or trapezius.; Other Names: handheld algometer (Wagner Instruments); the Pressure Algometer (Medoc, Ramat Yishai, Israel); Behavioral: Pressure pain thresholds (PPT); Pressure will be increased continually and participants will be instructed to press a button the first moment they feel pain from the pressure stimulus. The first threshold measurement will be used as a familiarization. The average threshold is calculated from three measurements.; Device: Thermal stimuli; The Thermal Sensory Analyzer (TSA-II or PATHWAY platform - Medoc, Ramat Yishai, Israel) will be used to safely deliver heat and cold stimuli. These devices can deliver relatively complex stimuli via computer control. All targeted stimulus temperatures will be less than 50°C, and participants will be free to remove their arm or leg at any time from the thermode. Noxious cold stimuli will also be delivered with a plastic water container or a water bath (FISHER, USA). Participants will be free to pull out of the water bath at any time.; Other Names: Thermal Sensory Analyzer (TSA-II or PATHWAY platform - Medoc, Ramat Yishai, Israel); Behavioral: Pain ratings; Pain intensity and pain unpleasantness ratings will be assessed.; Other Names: Numerical rating scale (ranging from 0- no pain/unpleasantness to- 100 the most intense/unpleasantness pain imaginable); mechanical and computerized visual analog scales (VAS which ranges between ''no pain sensation'' and ''most intense pain imaginable''); Behavioral: Conditioned pain modulation (CPM) response; The CPM paradigm assesses endogenous inhibitory pain modulation efficiency. CPM testing includes the application of a "test" stimulus without conditioning (control run, pressure pain thresholds) and a subsequent application of the same test stimulus together with a conditioning stimulus (conditioning run, a 60 second of foot immersion in cold water). The CPM response is the difference in the pressure pain thresholds between the control and the conditioning runs.; Behavioral: PedMIDAS (Pediatric Migraine Disability Assessment); Adolescents with migraine will complete questions regarding their headache frequency. Migraine disability will be assessed using PedMIDAS (Pediatric Migraine Disability Assessment). This self-reported questionnaire assesses the number of days that headaches affect participant's daily activities. This is a widely used, reliable and validated tool to assess migraine disability.; Diagnostic test: Hormonal assessment; Blood samples (approximetly 2 tablespoons) will be collected for analyses of sex hormone levels (e.g., testosterone, estradiol, progesterone).; Other: Pubertal status; Pubertal status will be assessed using the self-reported Physical Developmental Scale-Wave 3 survey, which allows for differentiation between pre-, early-, late-, and post-pubertal status. Early puberty is defined as a score of 3 and no menarche, mid-puberty is defined as 4 and no menarche, late pubertal is defined as a score of 7 points or less and with menarche, and post pubertal is defined as a score of 8 and menarche. For boys, pubertal maturation status will be determined by the Physical Development Scale using the body hair growth voice change and facial hair questions. Early puberty is defined as a score of 4-5, mid-puberty is defined as a score of 6-8, late pubertal is defined as a score of 9-11 points, and post pubertal is defined as a score of 12.
Placebo Comparator: Healthy control; Adolescents without a migraine diagnosis	Device: Pressure stimuli; Pressure stimuli will be applied by using a handheld algometer (Wagner Instruments) or the Pressure Algometer (Medoc, Ramat Yishai, Israel). These devices have a round probe that allows quantifying the amount of pressure that is being applied. The Pressure Algometer allows a real-time visual feedback to control and monitor applied pressure rates. Pressure will be applied to the lower leg, volar forearm, or trapezius.; Other Names: handheld algometer (Wagner Instruments); the Pressure Algometer (Medoc, Ramat Yishai, Israel); Behavioral: Pressure pain thresholds (PPT); Pressure will be increased continually and participants will be instructed to press a button the first moment they feel pain from the pressure stimulus. The first threshold measurement will be used as a familiarization. The average threshold is calculated from three measurements.; Device: Thermal stimuli; The Thermal Sensory Analyzer (TSA-II or PATHWAY platform - Medoc, Ramat Yishai, Israel) will be used to safely deliver heat and cold stimuli. These devices can deliver relatively complex stimuli via computer control. All targeted stimulus temperatures will be less than 50°C, and participants will be free to remove their arm or leg at any time from the thermode. Noxious cold stimuli will also be delivered with a plastic water container or a water bath (FISHER, USA). Participants will be free to pull out of the water bath at any time.; Other Names: Thermal Sensory Analyzer (TSA-II or PATHWAY platform - Medoc, Ramat Yishai, Israel); Behavioral: Pain ratings; Pain intensity and pain unpleasantness ratings will be assessed.; Other Names: Numerical rating scale (ranging from 0- no pain/unpleasantness to- 100 the most intense/unpleasantness pain imaginable); mechanical and computerized visual analog scales (VAS which ranges between ''no pain sensation'' and ''most intense pain imaginable''); Behavioral: Conditioned pain modulation (CPM) response; The CPM paradigm assesses endogenous inhibitory pain modulation efficiency. CPM testing includes the application of a "test" stimulus without conditioning (control run, pressure pain thresholds) and a subsequent application of the same test stimulus together with a conditioning stimulus (conditioning run, a 60 second of foot immersion in cold water). The CPM response is the difference in the pressure pain thresholds between the control and the conditioning runs.; Diagnostic test: Hormonal assessment; Blood samples (approximetly 2 tablespoons) will be collected for analyses of sex hormone levels (e.g., testosterone, estradiol, progesterone).; Other: Pubertal status; Pubertal status will be assessed using the self-reported Physical Developmental Scale-Wave 3 survey, which allows for differentiation between pre-, early-, late-, and post-pubertal status. Early puberty is defined as a score of 3 and no menarche, mid-puberty is defined as 4 and no menarche, late pubertal is defined as a score of 7 points or less and with menarche, and post pubertal is defined as a score of 8 and menarche. For boys, pubertal maturation status will be determined by the Physical Development Scale using the body hair growth voice change and facial hair questions. Early puberty is defined as a score of 4-5, mid-puberty is defined as a score of 6-8, late pubertal is defined as a score of 9-11 points, and post pubertal is defined as a score of 12.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Conditioned pain modulation (CPM) response	This psychophysical test examine the inhibitory pain modulation efficiency. In this test, pressure pain thresholds (measures by kilopascal) are assessed before and during immersion of the foot in cold water.	Baseline
Sex Hormones	Testosterone levels	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sex hormone assessments	Estrogen levels	Baseline
Migraine specific measures	Pediatric Migraine Disability Assessment (PedMIDAS) (range 0-540, higher values indicate more disability, with scores >50 considered as severe disability)	Baseline

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: International Headache Society
• Investigators: Principal Investigator: Hadas Nahman-Averbuch, PhD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): January 10, 2023
• Primary Completion (Actual): July 14, 2025
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: December 6, 2022
• First Submitted That Met QC Criteria: February 20, 2023
• First Posted (Actual): February 21, 2023

Study Record Updates

• Last Update Posted (Estimated): October 16, 2025
• Last Update Submitted That Met QC Criteria: October 14, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Keywords: pain; puberty; sex hormones
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain; Migraine Disorders; carboxypeptidase M
• Other Study ID Numbers: 202208057; Seed Pediatric Research Grant (Other Grant/Funding Number: International Headache Society)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No