Correspondence Address:
Dr. Nalini Mahajan
Mother and Child Hospital, D-59 Defence Colony, New Delhi - 110 024
India

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Biologically speaking, the dice is loaded against women. While it is possible for men to be fathers' way into old age, for women, reproductive capacity has already started waning when they cross the age of 35 and is severely limited after the age of 40. The reason for this phenomenon lies in the ability of the male germ cells to develop throughout adult life. Women, on the other hand, are thought to have a finite pool of oocytes at birth, which diminishes with age. This view was put forth by Waldeyer in 1870 and reaffirmed by other authors. It gained wide acceptance in the scientific community after a paper by Zuckerman in 1951,[1] which stated that neo-oogenesis did not occur postnatally in mammals.[2] This view remained unopposed till Johnson et al.[3] demonstrated oocyte-stem cells (OSCs) capable of generating new eggs, in adult mouse ovaries. These eggs underwent fertilization and produced viable offspring. These findings, though heavily debated, sparked extensive research because of their value in the fertility treatment of women with premature ovarian insufficiency (POI). White et al., 2012[4] demonstrated oocyte formation by active germ cells purified from ovaries of reproductive age women. In recent years, other authors[5] have provided convincing evidence of the presence of OSCs and their capability of developing into fertilizable oocytes and producing viable offspring in mice.

One of the major concerns has been extrapolation of animal studies to humans in view of the fact that follicular dynamics vary among species including mice and humans. Although animal studies have provided evidence of the existence of OSCs and postnatal oogenesis, human studies have not been able to provide indisputable proof of the same,[6] perhaps due to ethical and logistic constraints in human research. The possibility that there could be a resting pool of such cells in humans, however, has been acknowledged by many authors. These cells develop from progenitors in the tunica albugenia and epithelial crypts. Bone marrow stem cells too are considered to be a source of OSCs. It is believed that the quiescent OSCs respond to specific signals to get activated or they act as “helper cells” to the surviving follicles. The nature of these activating signals, however, remains elusive. Follicular stimulating hormone (FSH) has been considered to influence the activity of these cells, and FSH receptor 3 has been identified on very small embryonic-like stem cells (VSELs) in sheep.[7]

The review article by Bhartiya et al. in this issue of “The Onco Fertility Journal” discusses the role of VSELs and OSCs in the context of oncofertility. The authors suggest that VSELs survive oncotherapy and can regenerate the nonfunctional ovary. They further propose a supportive role for bone marrow mesenchymal stem cells (MSCs). MSCs provide paracrine support and have been shown to normalize ovarian function in rodents and possibly humans as well. A case report of successful delivery after transplanting autologous MSCs in the human ovary with premature ovarian failure supports this view. In the context of these findings, the author advocates a need to re-evaluate “ovarian tissue cryopreservation and re-implantation” as standard care for oncofertility patients with POI.

A myriad of questions remains unanswered – What is the role of OSCs in normal physiology? Why do they not start functioning when ovarian reserve begins to deplete with age, disease, or gonadotoxic therapy. Why only in vitro manipulation allows for growth? The most important question in the context of reproduction is whether they can be used effectively to extend the reproductive window in women with low ovarian reserve or those who have attained menopause? In older women, would the oocytes generated from these stem cells have increased aneuploidies?

The use of OSCs has the potential to revolutionize fertility therapies for women with decreased ovarian reserve due to medical or biological reasons. Their role in postmenopausal health care has also been envisaged. There is a definite need for more work in this area to help women widen their reproductive window and allow them to have genetic children when they desire. The burning question in all our minds remains – how long before the shift from bench-top to clinic?

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