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Objective:To discuss the potential for adverse consequences that could arise from the quest to prolong the functional life span of the human ovary. Methods:A series of arguments are presented that: (a) question the dogma that monthly ovulatory menstrual cycles are critical for women’s health; (b) review adverse consequences of decades of menstrual cyclicity; (c) review the evidence for a longevity benefit of ovarian steroid hormone treatment after the age at natural menopause has been achieved; and (d) utilize a mathematical model of ovarian follicle loss over time to raise the possibility that current strategies directed at delaying menopause might well backfire and in fact cause a woman to have a prolonged menopause transition. Results:Regular, monthly menstrual cycles have not been the reality for women for most of history. Rather, when not pregnant, lactational amenorrhea and nutritionally based hypothalamic amenorrhea were the norm for reproductive-aged women. Moreover, monthly menstrual cycles cause substantial morbidity for women during their reproductive years. Providing steroid hormones after menopause has failed to demonstrate an increase in the female life span. Restoring ovarian follicles either surgically or medically has a high probability of causing women to spend more years of life in the menopause transition. Conclusions:Strategies to prevent or delay menopause would benefit from careful consideration of unintended consequences as they are implemented. Directing treatment trials to those with the greatest chance for benefit should be undertaken before adopting this type of treatment for a broader population. 

Ovarian aging in women can be described as highly unpredictable within individuals but predictable across large populations. We showed previously that modeling an individual woman’s ovarian reserve of primordial follicles using mathematical random walks replicates the natural pattern of growing follicles exiting the reserve. Compiling many simulations yields the observed population distribution of the age at natural menopause (ANM). Here, we have probed how stochastic control of primordial follicle loss might relate to the distribution of the preceding menopausal transition (MT), when women begin to experience menstrual cycle irregularity. We show that identical random walk model conditions produce both the reported MT distribution and the ANM distribution when thresholds are set for growing follicle availability. The MT and ANM are shown to correspond to gaps when primordial follicles fail to grow for 7 and 12 days, respectively. Modeling growing follicle supply is shown to precisely recapitulate epidemiological data and provides quantitative criteria for the MT and ANM in humans.