Investigating Mechanisms of Ovarian Aging and Menopause Timing Using a Stochastic Approach

Although understanding the biology of ovarian aging and the timing of menopause is critical for supporting women's reproductive health, many aspects of these processes remain unclear. Stimulated by observations of transitions between different stages of functional units of ovarian units (follicles), a novel stochastic framework has recently been introduced. However, many important aspects of these biological phenomena have been overlooked. In this work, we present a theoretical investigation on synchronization in menopause timing, the role of follicle death, and the temporal dependence of transition rates. Our theoretical method views the depletion in the number of follicles as a multistage stochastic process governed by stage-specific transition and death rates. The narrow distributions of times before menopause are shown to be the result of synchronization when the transition rates between different stages become comparable. We also found that the deaths of the follicles, known as atresia, accelerate the maturation of the follicles. It is suggested that this might be a possible explanation of oversupply when women are born with many more follicles than they need for reproduction. Furthermore, we developed a novel stochastic model of ovarian aging with time-dependent transition rates, and it is shown that this method accounts well for the available data on follicle depletion. Our analysis suggests that there is a specific age at which follicle depletion accelerates. The presented theoretical approach offers novel insights into the mechanisms of complex biological processes, suggesting potential directions for future improvements in women's health.