BME PHD Prospectus Presentation: Caitlin Colicchio

Title: " Loss of Hormonal Cyclicity as a Driver of Impaired Mechanical Adaption in Tendon"

Advisory Committee: Irving Bigio, PhD – BU BME (Advisor) Darren Roblyer, PhD – BU BME (Chair) Michelle Sander, PhD – BU ECE

Abstract: Sex hormones are known to modulate collagen turnover and tenocyte behavior, and prior work has established that cyclical hormone fluctuations drive phase-dependent changes in tendon and ligament structure and function. However, most models of hormonal influence on tendon remain reductionist, relying on constant hormone exposure or ovariectomy-induced hormone depletion, and fail to capture the dynamic, fluctuating nature of estrogen and progesterone across the cycle, leaving how cyclicity itself shapes tendon’s intrinsic mechanosensing uncharacterized. This gap is especially consequential across the menopausal transition: despite affecting over one billion women worldwide, the musculoskeletal consequences of menopause remain poorly understood and undertreated. Female tendon injury rates climb dramatically during the perimenopausal years, and although exercise is widely prescribed to preserve musculoskeletal health, it appears to lose its protective benefit in peri- and postmenopausal women, who report reduced training gains alongside elevated injury risk. How this loss of cyclicity disrupts tendon’s adaptive response to exercise remains uncharacterized, and whether hormone replacement therapy (HRT) can restore it is entirely unexplored. Our preliminary data demonstrate that physiologic hormonal cyclicity drives distinct extracellular matrix (ECM) remodeling and mechanotransduction profiles compared to continuous hormone or no hormone treatment, suggesting that loss of coordinated hormonal cyclicity, rather than hormone loss alone, may be the key driver of menopausal tendon dysfunction. The 4-vinylcyclohexene diepoxide (VCD) mouse model produces a staged, physiologic transition through menopause, offering a uniquely translatable platform for studying these hormonal dynamics and testing this hypothesis in vivo. Therefore, the overall objective of this project is to define how hormonal cyclicity and its loss shape tendon’s adaptive response to exercise, and to determine whether HRT can restore it across the menopausal transition. With this proposal, I aim to (1) define how hormonal cyclicity shapes tendon’s adaptive machinery, spanning early mechanosensing, ECM remodeling, and mechanical adaptation, using tendon explants cultured under a simulated estrous cycle, (2) determine how loss of cyclicity during the menopausal transition impairs tendon's acute and chronic adaptive responses to exercise, using sedentary and exercised VCD mice across defined reproductive stages, and (3) restore tendon’s adaptive responses to exercise at the menopausal inflection point using HRT in VCD mice, testing whether HRT rescues all or some components of this adaptive machinery. This work will be the first to establish hormonal cyclicity, rather than hormone level or presence alone, as the key driver of tendon’s adaptive capacity, and to test whether restoring it with HRT can rescue exercise-induced adaptation across the menopausal transition. These insights will inform the development of temporally optimized hormonal interventions and stage-specific exercise guidelines to reduce injury risk in menopausal women.