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Abstract Women are born with hundreds of thousands to over a million primordial ovarian follicles (PFs) in their ovarian reserve. However, only a few hundred PFs will ever ovulate and produce a mature egg. Why are hundreds of thousands of PFs endowed around the time of birth when far fewer follicles are required for ongoing ovarian endocrine function and only a few hundred will survive to ovulate? Recent experimental, bioinformatics, and mathematical analyses support the hypothesis that PF growth activation (PFGA) is inherently stochastic. In this paper, we propose that the oversupply of PFs at birth enables a simple stochastic PFGA mechanism to yield a steady supply of growing follicles that lasts for several decades. Assuming stochastic PFGA, we apply extreme value theory to histological PF count data to show that the supply of growing follicles is remarkably robust to a variety of perturbations and that the timing of ovarian function cessation (age of natural menopause) is surprisingly tightly controlled. Though stochasticity is often viewed as an obstacle in physiology and PF oversupply has been called “wasteful,” this analysis suggests that stochastic PFGA and PF oversupply function together to ensure robust and reliable female reproductive aging.
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Mathematical recapitulation of the end stages of human ovarian aging
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.
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- PAR ID:
- 10505349
- Publisher / Repository:
- American Association for the Advancement of Science
- Date Published:
- Journal Name:
- Science Advances
- Volume:
- 10
- Issue:
- 2
- ISSN:
- 2375-2548
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract BACKGROUNDWomen are increasingly choosing to delay childbirth, and those with low ovarian reserves indicative of primary ovarian insufficiency are at risk for sub- and infertility and also the early onset of menopause. Experimental strategies that promise to extend the duration of ovarian function in women are currently being developed. One strategy is to slow the rate of loss of existing primordial follicles (PFs), and a second is to increase, or ‘boost’, the number of autologous PFs in the human ovary. In both cases, the duration of ovarian function would be expected to be lengthened, and menopause would be delayed. This might be accompanied by an extended production of mature oocytes of sufficient quality to extend the fertile lifespan. OBJECTIVE AND RATIONALEIn this work, we consider how slowing physiological ovarian aging might improve the health and well-being of patients, and summarize the current state-of-the-art of approaches being developed. We then use mathematical modeling to determine how interventions are likely to influence the duration of ovarian function quantitatively. Finally, we consider efficacy benchmarks that should be achieved so that individuals will benefit, and propose criteria that could be used to monitor ongoing efficacy in different patients as these strategies are being validated. SEARCH METHODSCurrent methods to estimate the size of the ovarian reserve and its relationship to the timing of the menopausal transition and menopause were compiled, and publications establishing methods designed to slow loss of the ovarian reserve or to deliver additional ovarian PFs to patients were identified. OUTCOMESWe review our current understanding of the consequences of reproductive aging in women, and compare different approaches that may extend ovarian function in women at risk for POI. We also provide modeling of primordial reserve decay in the presence of therapies that slow PF loss or boost PF numbers. An interactive online tool is provided that estimates how different interventions would impact the duration of ovarian function across the natural population. Modeling output shows that treatments that slow PF loss would need to be applied as early as possible and for many years to achieve significant delay of menopause. In contrast, treatments that add additional PFs should occur as late as possible relative to the onset of menopause. Combined approaches slowing ovarian reserve loss while also boosting numbers of (new) PFs would likely offer some additional benefits in delaying menopause. WIDER IMPLICATIONSExtending ovarian function, and perhaps the fertile lifespan, is on the horizon for at least some patients. Modeling ovarian aging with and without such interventions complements and helps guide the clinical approaches that will achieve this goal. REGISTRATION NUMBERNot applicable.more » « less
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OBJECTIVE: Rapamycin prolongs reproductive lifespan in mice by halting primordial follicle activation. The impact of rapamycin on the preantral follicle pool and senescence markers during ovarian aging in macaques was evaluated. MATERIALS AND METHODS: One ovary was removed from young (n=2, 6–9 yr) and old (n=2, 17–21 yr) adult female rhesus macaques during a normal menstrual cycle (pre-treatment). The remaining ovary was obtained after animals were treated with rapamycin (bid, IM, 0.02mg/kg) for 10 months. Ovaries were fixed and serially sectioned for follicle counting (each 10th section, 15-39 sections/ovary). Immunohistochemical analyses were performed for anti-Mullerian hormone (AMH) and cellular senescence markers p16, p53, and p21 (1 slide/ovary). Qualitative comparisons were made due to the small sample size. RESULTS: The primordial follicle pool was decreased in young (3,939 pre-treatment vs. 2,219 post-treatment), but similar in old (555 pre- vs. 574 post-treatment) females after rapamycin. The number of transitional primordial follicles was greater before rapamycin than after in both young (14,920 vs. 4,924) and old (1,915 vs. 1,311) females. The number of primary follicles before (2,617) rapamycin was greater than after (560) in young and old females (518 pre- vs. 428 post-treatment). A similar proportion of follicles positive for p16 was seen before and after rapamycin in both young and old females. Similar findings were also observed for AMH, except there are fewer positive follicles in the rapamycin-treated older group. The proportion of follicles staining positive for both p53 and p21 was increased in both young and old monkeys after treatment. CONCLUSIONS: Rapamycin had no impact on the primordial and primary follicle pools in old female macaques while unexpectedly decreasing both pools in young females. While the number of p16-positive follicles was unaffected by rapamycin treatment, the number of p53 and p21-positive follicles was increased by treatment in both age cohorts. IMPACT STATEMENT: At the dose and treatment interval used, rapamycin does not appear to suppress follicular activation and has mixed effects on senescence markers in aging nonhuman primate ovaries.more » « less
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1126/sciadv.adj4490
