Computational Modeling of the Biphasic Depletion of Ovarian Follicle Reserve and the Chemical Effects on Ovarian Aging

Abstract

IntroductionHuman ovaries begin development in utero. Through oogenesis, the numbers of oocytes and primordial follicles peak to a few million during fetal development, then decline to hundreds of thousands per ovary at birth. These primordial follicles do not regenerate and are thus regarded as the ovarian reserve. Over the life course, the reserve continues to deplete, due to atresia and activation, until menopause when about 1000 primordial follicles remain. Exposure to chemotherapy drugs and environmental pollutants can accelerate follicular depletion potentially leading to a greater risk of early menopause, primary ovarian insufficiency (POI), and infertility. Physiologically, the ovarian reserve is depleted in a seemingly biphasic pattern - a slow steady decline from birth to mid-30s, followed by a faster decline to menopause which typically occurs around age 50 years. While this depletion pattern has been described with empirical mathematical formulations, rarely is it modeled mechanistically. A mechanic model that can characterize the dynamics of follicular depletion throughout the life course will help researchers better understand and predict the impact of chemical exposures on ovarian aging. MethodsHere we propose a minimal mechanistic model, which includes (1) a zero-order feedforward inhibition of primordial follicle activation by a local autocrine/paracrine inhibitory factor secreted by the primordial follicles, and (2) a high-gain feedback inhibition of primordial follicle activation by the anti-Mullerian hormone (AMH) secreted by the growing (primary, secondary, and early antral) follicles. The model is configured such that the two regulatory processes prevent primordial follicles from premature overactivation in early and late reproductive life stages, respectively. Two exposure scenarios - chemo-drugs/radiation and tobacco smoke - are presented to demonstrate predictive robustness and biological plausibility of chemically induced increases in cellular atresia. ResultsOur model recapitulates the biphasic depletion curve and predicts a constant supply of growing follicles through most of the active reproductive lifespan. This model predicts that the size of the initial primordial follicle pool plays the most significant role in determining menopausal age and suggests that unilateral ovariectomy may have a more attenuated effect than expected. Simulations of transient exposure to chemotherapy drugs provide an exposure example for promoting atresia of primordial and/or growing follicles and suggest exposure at earlier ages have greater impact on ovarian reserve and menopausal timing than exposure at later ages. Also, simulations of chronic chemical exposures suggest that chemicals which directly promote primordial follicle atresia are more damaging than chemicals directly promoting growing follicle atresia or inhibiting AMH, potentially leading to earlier age at menopause. A specific scenario of chronic exposure to cigarette smoke of various intensities was simulated to validate the prediction power of the model. ConclusionsThe ovary may have compensatory factors to extend reproductive age as long as possible amid insults that reduce the primordial follicle pool. The timing of these insults are likely an important variable. Future elaborations of such mechanistically based computational modeling with integration of in vitro toxicity testing data may help scaling efforts in predicting the implications of reproductive toxicants on ovarian aging.