The paradigm that the mammalian ovarian reserve is fixed at birth dates back to a nineteenth century hypothesis by Waldeyer in 1870, which was reaffirmed by Zuckerman in 1951 (reviewed in Tilly et al., 2009). However, there is mounting evidence that this is only part of the story, and that it may be possible to replenish the ovarian follicle pool due to the presence of a population of oogonial stem cells (OSC) in adult ovaries (Niikura et al., 2009). It is likely that both of these explanations are true in part; there is a fixed number of follicles at birth, which declines until exhaustion (typically 40+ years of age in the human), but that a population of OSC co-exist in the ovary and may be activated under specific circumstances (Tilly and Telfer, 2009). However, spontaneous reactivation of OSCs is not yet believed to occur naturally in vivo in the adult human ovary. This is one principle that underpins the notion of ovarian rejuvenation.
As an illustration of this concept, mice rendered sterile from chemotherapeutic drugs can have fertility restored and can produce viable offspring through natural mating after undergoing an OSC transplant from neonatal or adult mouse ovaries (Zou et al., 2009). It was further demonstrated that when ovarian tissue containing premeiotic germ cells from aged mice was transplanted into young host mice, the germ cells produced NOBOX-expressing oocytes and formed follicles (Niikura et al., 2009). Combined, these studies show OSC transplantation may restore fertility and that it may be possible to produce oocytes from OSC from aged mammalian ovaries in the correct milieux.
Although data from animal models support the notion of OSCs, the presence of equivalent stem cell populations in humans remains disputed. For example, Virant-Klun et al. (2008) confirmed that ovarian stem-like cells were present on the surface epithelium of post-menopausal women and women with premature ovarian failure (POF), which aligns with the reported location of OSC in the ovaries of juvenile and young-adult mice (Tilly and Telfer, 2009). By contrast, when analysing the cell populations in the human ovarian cortex, Wagner et al. (2020) were unable to identify a population of germline stem cells. Of course, it must be acknowledged that studies on normal ovarian function in humans is rather constrained since substantial ovarian tissue from healthy, reproductive-aged women is rarely available. Furthermore, tissue from dysfunctional ovaries may not exhibit the full range of physiological function, and biopsies may not be reflective of the whole ovary as stem cells may not be uniformly spread (Horan and Williams, 2017). These factors make it challenging to determine definitively if a population of stem cells is present within the adult ovary.
If present, ovarian OSC may offer the potential for women experiencing ovarian failure as a result of menopause or POF to be treated for their infertility beyond the only current option of IVF using a donor egg. This has provided an underpinning of attempts to initiate ovarian rejuvenation in clinical settings, including investigating the utility of PRP in four pilot studies of different reproductive pathologies: POI, poor ovarian responders (POR), perimenopause and menopause (Sfakianoudis et al., 2020b).
Hum Reprod. 2021;36(7):1737-1750. © 2021 Oxford University Press