Upon puberty, a group of immature follicles is sequentially activated to resume growth with every reproductive cycle and a single dominant follicle eventually emerges, ovulates, and then involutes to allow selection of the next group of follicles. The ovary contains a large number of dormant immature follicles, the organ’s functional units, each accommodating a single oocyte and residing on the periphery of the ovary. Ovary, extracellular matrix, hormone replacement therapy, aging, fertility preservation, mechanobiology Introduction Such a stiff niche is nonpermissive to prepubertal follicle activation and growth, and is more inclined to quiescence. Closer examination of the ECM surrounding follicles from the primordial to the secondary stage, both before and after puberty, points to high levels of mechanical stress placed on prepubertal follicles compared to the more compliant ECM around reproductive-age follicles, as suggested by the higher collagen levels and lower elastin content detected mainly around primordial ( P < 0.0001 P < 0.0001, respectively) and primary ( P < 0.0001 P < 0.001, respectively) follicles. This decline partially accounts for the decrease in EMILIN-1 ( r = 0.4149 P = 0.00059). In this context, elevated GAG values are suspected to participate in hampering formation of the fibrillin-1 network ( r = −0.2475 P = 0.04687), which explains its decline over time. Higher GAG levels were found in adult ovaries compared to prepubertal ovaries ( P < 0.05), suggesting changes in tissue ultrastructure and elasticity with age. Interestingly, HRT appears to affect elastin presence in ovarian tissue, since a significantly higher ( P < 0.05) proportion of elastin was detected in biopsies from menopausal women taking HRT compared to those not. Interestingly, collagen and elastin reached their peak in reproductive-age women compared to prepubertal ( P < 0.01 P = 0.262) and menopausal subjects with ( P = 0.706 P < 0.01) and without ( P = 0.987 P = 0.610) HRT, indicating a positive impact of secreted estrogen and hormone treatment on collagen and elastin preservation. While collagen levels increased with age, fibrillin-1 and EMILIN-1 declined. Evidence supporting a role for the physical environment in follicle activation was provided in clinical practice by ovarian tissue fragmentation, which promoted actin polymerization and disrupted ovarian Hippo signaling, leading to increased expression of downstream growth factors, promotion of follicle growth and generation of mature oocytes. Thus, changes in the rigidity of the ovarian ECM have a direct effect on follicle behavior. As growing follicles migrate to the medulla of the ovary, they encounter a softer, more pliant ECM, allowing expansion and development. Indeed, while the localization of primordial follicles in the collagen-rich ovarian cortex offers a rigid physical environment that supports follicle architecture and probably plays a role in their survival, ovarian extracellular matrix (ECM) stiffness limits follicle expansion and hence oocyte maturation, maintaining follicles in their quiescent state. The mechanobiology of the human ovary and dynamic reciprocity that exists between ovarian cells and their microenvironment is of high importance.