Sex Hormones & Exercise in the Musculoskeletal System: From Signaling to Structure and Function.

Sex steroid hormones, such as estrogen, progesterone, and testosterone, are primarily known as critical regulators of reproductive function in both males and females. However, increasing evidence indicates that fluctuating levels of sex hormones also affect non-reproductive organs, including tissues in the musculoskeletal system. Observations from muscle and bone literature support a model in which hormonal state modulates exercise-induced mechanotransduction and downstream extracellular matrix (ECM) remodeling. However, soft connective tissues - cartilage, meniscus, tendon, ligament, intervertebral disc - are often overlooked, despite being the primary sites of career-ending sports injuries and chronic degeneration. This review focuses on these tissues, aiming to examine how sex hormones and other sex-specific molecules critically regulate the process of exercise adaptation at the tissue level. We first outline sex steroid biosynthesis, bioavailability, and receptor mechanisms and then examine how steroids intersect with mechanosensing and mechanotransduction. Looking further downstream, we then assess how hormonal state regulates ECM turnover and functional adaptations. We propose novel connections and mechanisms by which sex hormones and other sex-specific molecules determine load-induced responses via specific mechanotransduction pathways and through ECM remodeling. We conclude by outlining open questions and experimental needs that would aid in establishing causal relationships between sex hormones and exercise responses in soft musculoskeletal tissues.