Effect of Menstrual Cycle and Hormonal Contraception on Musculoskeletal Health and Performance: Protocol for a Prospective Cohort Design and Cross-Sectional Comparison
Authors: Myers Sarah J , Knight Rebecca L , Wardle Sophie L , Waldock Kirsty AM , O'Leary Thomas J , Jones Richard K , Muckelt Paul E , Eisenhauer Anton , Tang Jonathan CY , Fraser William D , Greeves Julie P 
Published: July 2024

Background
Women of reproductive age experience cyclical variation in the female sex steroid hormones 17β-estradiol and progesterone during the menstrual cycle that is attenuated by some hormonal contraceptives. Estrogens perform a primary function in sexual development and reproduction but have nonreproductive effects on bone, muscle, and sinew tissues (ie, ligaments and tendons), which may influence injury risk and physical performance.

Objective
The purpose of the study is to understand the effect of the menstrual cycle and hormonal contraceptive use on bone and calcium metabolism, and musculoskeletal health and performance.

Methods
A total of 5 cohorts of physically active women (aged 18-40 years) will be recruited to participate: eumenorrheic, nonhormonal contraceptive users (n=20); combined oral contraceptive pill (COCP) users (n=20); hormonal implant users (n=20); hormonal intrauterine system users (n=20); and hormonal injection users (n=20). Participants must have been using the COCP and implant for at least 1 year and the intrauterine system and injection for at least 2 years. First-void urine samples and fasted blood samples will be collected for biochemical analysis of calcium and bone metabolism, hormones, and metabolic markers. Knee extensor and flexor strength will be measured using an isometric dynamometer, and lower limb tendon and stiffness, tone, and elasticity will be measured using a Myoton device. Functional movement will be assessed using a single-leg drop to assess the frontal plane projection angle and the qualitative assessment of single leg loading. Bone density and macro- and microstructure will be measured using ultrasound, dual-energy x-ray absorptiometry, and high-resolution peripheral quantitative computed tomography. Skeletal material properties will be estimated from reference point indentation, performed on the flat surface of the medial tibia diaphysis. Body composition will be assessed by dual-energy x-ray absorptiometry. The differences in outcome measures between the hormonal contraceptive groups will be analyzed in a one-way between-group analysis of covariance. Within the eumenorrheic group, the influence of the menstrual cycle on outcome measures will be assessed using a linear mixed effects model. Within the COCP group, differences across 2 time points will be analyzed using the paired-samples 2-tailed t test.

Results
The research was funded in January 2020, and data collection started in January 2022, with a projected data collection completion date of August 2024. The number of participants who have consented at the point of manuscript submission is 66. It is expected that all data analysis will be completed and results published by the end of 2024.

Conclusions
Understanding the effects of the menstrual cycle and hormonal contraception on musculoskeletal health and performance will inform contraceptive choices for physically active women to manage injury risk.

Trial Registration
ClinicalTrials.gov NCT05587920; https://classic.clinicaltrials.gov/ct2/show/NCT05587920

International Registered Report Identifier (IRRID)
DERR1-10.2196/50542