Exploring the Modulatory Role of Sex Hormones Along the Neuromechanical Axis in Females (EMRSHN)

EMRSHN 2: Exploring the Modulatory Role of Sex Hormones Along the Neuromechanical Axis in Females

The goal of this project is to test our central hypothesis that changes in sex hormone concentration result in changes to the basic elements of motor control - at multiple levels, from the musculotendinous unit to motor control circuitry. Under Aim 1 the investigator will determine the influence of sex hormone fluctuations on the muscle stretch reflex during active and passive states, and the time lag between hormone concentration changes and the reflex response. The investigator will use a technically simple assessment that could be implemented in the field. Under Aim 2 the investigator will determine the influence of sex hormone fluctuations on spinal motor neuron excitability using H-reflex as a probe and the simultaneous change in the muscle mechanics using muscle twitch response. Aims 1 & 2 will include a focus on the differential role of oral contraceptives. In Aim 3 the investigator will use paired-pulse transcranial magnetic stimulation during active contraction to determine the influence of sex hormone fluctuation.

Study Overview

• Status: Completed
• Conditions: Role of Sex Hormones Along the Neuromechanical Axis
• Intervention / Treatment: Device: Transcranial Magnetic Stimulation Device

• Study Type: Observational
• Enrollment (Actual): 102
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 39 years (Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Non oral contraceptive group (NOC): Healthy females at 18-39 years old, who are eumenorrheic (regular monthly cycles of 24-35 days) and moderately active;

Oral contraceptive group (OC): Healthy females at 18-39 years old, who are on a stable hormonal contraceptive regimen for 6 months (oral, transdermal or vaginal) and moderately active;

Male group: Healthy males at 18-39 years old.

Description

Inclusion Criteria:

• Females: ages 18-39 years, who are eumenorrheic (regular monthly cycles of 24-35 days) or on a stable hormonal contraceptive regimen for 6 months (oral, transdermal or vaginal), no history of pregnancy, moderately active (less than 7 hours of vigorous physical activity per week)
• Males: Ages 18-39

Exclusion Criteria:

• History of musculoskeletal or orthopedic injury of the spine, hip, knee, ankle or foot, history of neurological injury of the peripheral or central nervous system, current smoker, history of disordered eating, history of stress fracture in the lower limb, history of a connective tissue disorder (Marfan's syndrome, Ehlers-Danlos disease).
• For female participants only: Point of care screening for anemia will be completed, and individuals with hemoglobin levels <11.6 g/dl will be excluded from participating in the study.
• Specific exclusion criteria for TMS (male and female): pacemaker, metal implants in the head region, history of epilepsy or seizures, skull fractures or skull deficits, concussion within the last 6 months, unexplained recurring headaches, medications that lower seizure threshold, and pregnancy.
• Additional exclusion criteria for female participants: History of menstrual dysfunction (primary or secondary amenorrhea, oligomenorrhea, anovulatory cycles, polycystic ovarian disease), current or past pregnancy, started or stopped taking oral contraceptives within the previous 6 months, exercise vigorously more than 7 hours per week or currently participating in competitive level sports. The reason for excluding highly active or competitive athletes is due to the high rate of undiagnosed menstrual dysfunction in females of this population.
• This study will not include: adults unable to consent, Individuals who are not yet adults (infants, children, teenagers), pregnant women or prisoners.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Non-Oral Contraceptive (NOC); Females ages 18-39 years, who are eumenorrheic (regular monthly cycles of 24-35 days) and moderately active. Exclusion criteria: History of musculoskeletal or orthopedic injury of the spine, hip, knee, ankle or foot, history of neurological injury of the peripheral or central nervous system, history of disordered eating, of a connective tissue disorder (Marfan's syndrome, Ehlers-Danlos disease), history of or current diabetes, pacemaker, metal implants in the head region, history of epilepsy or seizures, skull fractures or skull deficits, concussion within the last 6 months, unexplained recurring headaches, medications that lower seizure threshold, and pregnancy.
Oral Contraceptive ( OC); Females: ages 18-39 years, who are on a stable hormonal contraceptive regimen for 6 months (oral, transdermal or vaginal) and moderately active. Exclusion criteria: History of musculoskeletal or orthopedic injury of the spine, hip, knee, ankle or foot, history of neurological injury of the peripheral or central nervous system, history of disordered eating, of a connective tissue disorder (Marfan's syndrome, Ehlers-Danlos disease), history of or current diabetes, started or stopped taking oral contraceptives within the previous 6 months, participate in high impact endurance training (i.e. pre-marathon training, body building), or currently participating in competitive level sports.
Male; Males: Ages 18-39. Exclusion criteria: History of musculoskeletal or orthopedic injury of the spine, hip, knee, ankle or foot, history of neurological injury of the peripheral or central nervous system, history of disordered eating, of a connective tissue disorder (Marfan's syndrome, Ehlers-Danlos disease), history of or current diabetes, pacemaker, metal implants in the head region, history of epilepsy or seizures, skull fractures or skull deficits, concussion within the last 6 months, unexplained recurring headaches, and medications that lower seizure threshold.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Spinal Motor Neuron Excitability in Non Oral Contraceptive User	The spinal motor neuron excitability was measured by calculating the ratio between the maximum peak-to-peak value of H reflex and the maximum peak-to-peak value of M wave. Change was evaluated by regressing the ratio simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. Average and standard deviation for each menstrual phase is reported.	Follicular, Luteal
Normalized Conditioned Motor Evoked Potential in Male and Female	The conditioned motor evoked potential (MEP) at each inter-stimulus interval (ISI) was normalized to MEP obtained from unconditioned stimulation. The difference between male and female groups was evaluated using a 2 (male vs. female) x 7 (ISI) repeated measures ANOVA. Average and standard deviation for each ISI reported.	menses period for female, day 1 for male
Change in Spinal Motor Neuron Excitability in Oral Contraceptive User	The spinal motor neuron excitability was measured by calculating the ratio between the maximum peak-to-peak value of H reflex and the maximum peak-to-peak value of M wave. Change was evaluated by regressing the ratio simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. Average and standard deviation for active and inactive pill phase are reported.	Active pill, Inactive pill
Changes in Short-interval Intracortical Inhibition (SICI) During the Follicular Phase	The conditioned motor evoked potential (MEP) at each inter-stimulus interval (ISI) was normalized to MEP obtained from unconditioned stimulation. Change was evaluated by regressing the normalized conditioned motor evoked potential amplitude at each ISI with estradiol concentration. Average and standard deviation for each ISI reported.	day 1 menses up to day with highest estradiol concentration
Change in Stretch Reflex at Relaxed State	Muscle stretch reflex (MSR) was calculated by dividing the root mean squared (RMS) value of the electromyogram (EMG) response with the RMS of the muscle's EMG during maximal voluntary contraction and the force of the tapper used to elicit the reflex. Change was evaluated by regressing the ratio simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. Average and standard deviation for each menstrual phase is reported.	Follicular, Luteal
Changes in Intracortical Facilitation (ICF) During the Follicular Phase	The conditioned motor evoked potential (MEP) at each inter-stimulus interval (ISI) was normalized to MEP obtained from unconditioned stimulation. Change was evaluated by regressing the normalized conditioned motor evoked potential amplitude at each ISI with estradiol concentration. Average and standard deviation for each ISI reported.	day 1 menses up to day with highest estradiol concentration
Change in Stretch Reflex at Active State	Muscle stretch reflex (MSR) was calculated by dividing the root mean squared (RMS) value of the electromyogram (EMG) response with the RMS of the muscle's EMG during maximal voluntary contraction and the force of the tapper used to elicit the reflex. Change was evaluated by regressing the ratio simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. Average and standard deviation for each menstrual phase is reported.	Follicular, Luteal

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Steadiness of Isometric Force Production at 20% of Maximum Voluntary Contraction in Non Oral Contraceptive User	Steadiness of the exerted force is quantified using coefficient of variation. Change was evaluated by regressing the steadiness simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) follicular phase, and (2) luteal phase. Average and standard deviation for each phase is reported.	Follicular, Luteal
Change in Flexion Reflex Root Mean Squared Value in Non Oral Contraceptive User	The root mean squared (RMS) value were calculated and averaged for each testing visit. Change was evaluated by regressing the RMS simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) follicular phase, and (2) luteal phase. Average and standard deviation for each phase is reported.	Follicular, Luteal
Change in Flexion Reflex Duration in Non Oral Contraceptive User	The duration were calculated and averaged for each testing visit. Change was evaluated by regressing the duration simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) follicular phase, and (2) luteal phase. Average and standard deviation for each phase is reported.	Follicular, Luteal
Change in Flexion Reflex Latency in Non Oral Contraceptive User	The latency measured from the onset of the stimulus were calculated and averaged for each testing visit. Change was evaluated by regressing the latency simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) follicular phase, and (2) luteal phase. Average and standard deviation for each phase is reported.	Follicular, Luteal
Change in Flexion Reflex Root Mean Squared Value in Oral Contraceptive User	The root mean squared (RMS) value were calculated and averaged for each testing visit. Change was evaluated by regressing the RMS simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) active pill, and (2) inactive pill. Average and standard deviation for each phase is reported.	Active pill, Inactive pill
Change in Flexion Reflex Duration in Oral Contraceptive User	The duration were calculated and averaged for each testing visit. Change was evaluated by regressing the duration simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) active pill, and (2) inactive pill. Average and standard deviation for each phase is reported.	Active pill, Inactive pill
Change in Flexion Reflex Latency in Oral Contraceptive User	The latency measured from the onset of the stimulus were calculated and averaged for each testing visit. Change was evaluated by regressing the latency simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) active pill, and (2) inactive pill. Average and standard deviation for each phase is reported.	Active pill, Inactive pill
Change in Steadiness of Isometric Force Production at 20% of Maximum Voluntary Contraction in Oral Contraceptive User	Steadiness of the exerted force is quantified using coefficient of variation. Change was evaluated by regressing the steadiness simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) active pill, and (2) inactive pill. Average and standard deviation for each phase is reported.	Active pill, Inactive pill

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Muscle Twitch Peak Torque in Non Oral Contraceptive User	Change was evaluated by regressing the peak torque simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) follicular phase, and (2) luteal phase. Average and standard deviation for each phase is reported.	Follicular, Luteal
Number of Positive Ovulation	Urinary ovulation kits is used to verify the ovulatory cycles and identify the approximate day of ovulation of the NOC group.	Follicular
Change in Muscle Twitch Time to Peak Torque in Non Oral Contraceptive User	Change was evaluated by regressing the time to peak torque simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) follicular phase, and (2) luteal phase. Average and standard deviation for each phase is reported.	Follicular, Luteal
Change in Muscle Twitch Half Relaxation Time in Non Oral Contraceptive User	Change was evaluated by regressing the half relaxation time simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) follicular phase, and (2) luteal phase. Average and standard deviation for each phase is reported.	Follicular, Luteal
Change in Muscle Twitch Peak Torque in Oral Contraceptive User	Change was evaluated by regressing the peak torque simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) active pill, and (2) inactive pill. Average and standard deviation for each phase is reported.	Active pill, Inactive pill
Change in Muscle Twitch Time to Peak Torque in Oral Contraceptive User	Change was evaluated by regressing the time to peak torque simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) active pill, and (2) inactive pill. Average and standard deviation for each phase is reported.	Active pill, Inactive pill
Change in Muscle Twitch Half Relaxation Time in Oral Contraceptive User	Change was evaluated by regressing the half relaxation time simultaneously on estradiol and progesterone concentrations, and estradiol x progesterone interaction. The analyses was performed during (1) active pill, and (2) inactive pill. Average and standard deviation for each phase is reported.	Active pill, Inactive pill

Collaborators and Investigators

• Sponsor: University of Texas Southwestern Medical Center
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Investigators: Principal Investigator: Yasin Dhaher, Ph.D., University of Texas Southwestern Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): April 12, 2019
• Primary Completion (Actual): April 30, 2024
• Study Completion (Actual): April 30, 2024

Study Registration Dates

• First Submitted: April 22, 2019
• First Submitted That Met QC Criteria: May 9, 2019
• First Posted (Actual): May 13, 2019

Study Record Updates

• Last Update Posted (Actual): February 9, 2026
• Last Update Submitted That Met QC Criteria: January 15, 2026
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Sex Hormones
• Other Study ID Numbers: STU-2018-0192; 1R01AR069176-01A1 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes