The Effect of Sex Hormones on Joint Ligament Properties: A Systematic Review and Meta-analysis

BACKGROUND: Sex differences exist in injury rates, and one contributing factor may be sex hormone effects on the musculoskeletal system. PURPOSE/HYPOTHESIS: The goal of this systematic review and meta-analysis was to understand the effects of sex hormones on ligaments in females as determined by preclinical and clinical studies. The hypothesis was that sex hormones would affect ligament mechanical properties, histological features, cellular function, and clinically measurable outcomes. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 4. METHODS: A literature search of PubMed, PEDro, CINAHL, and CENTRAL was performed to identify preclinical and clinical studies assessing sex hormone effects on ligament properties. Overall, 2 independent reviewers performed title, abstract, and full-text screening. Rigor and reproducibility were assessed using the ARRIVE guidelines and the modified Downs and Black checklist. Meta-analyses were also performed. RESULTS: There were 54 articles included in this review. The majority of studies focused on the anterior cruciate ligament (ACL; n = 27), the menstrual cycle (n = 23), and 17β-estradiol (n = 35). Meta-analyses revealed that there was no effect of the menstrual cycle on knee laxity or anterior tibial translation but that 17β-estradiol decreased the production of types I and III procollagen in ACL fibroblasts in vitro. In examining other ligaments, data suggest that sex hormone changes may affect the mechanical and cellular properties of the medial collateral ligament, intrapubic ligaments, hip ligaments, and ligamentum flavum. Additionally, the literature suggests that hormonal shifts that occur with oral contraceptive pill use, pregnancy, and menopause can affect ligament properties. These effects appear to be mediated, at least in part, by the hormone relaxin. CONCLUSION: Of the sex hormones examined in this body of literature, 17β-estradiol and relaxin appear to have the most effect on both the mechanical and cellular properties of ligaments in females. The ACL, medial collateral ligament, intrapubic ligaments, hip ligaments, and ligamentum flavum may be impacted by changes in sex hormone concentrations. The menstrual cycle does not likely affect ligament laxity in a clinically meaningful way, but pregnancy, oral contraceptive pill use, and menopause may.