Manipulating ovarian aging: A new frontier in fertility preservation

the premature and age-induced ovarian failure are associated with significant medical and quality of life complications. Moreover, millions of children and adults suffer from iatrogenically-induced premature gonadal failure as a result of chemotherapy treatments. In the case of chemotherapy, commonly used cancer drugs such as doxorubicin or cyclophosphamide result in apoptotic death of primordial follicle reserve [1-3], probably by inducing double strand DNA breaks concurrent with intense activation of ATM-mediated DNA repair pathways (unpublished data). Clinically, females who receive similar cancer drugs and who do not immediately become menopausal will experience premature menopause because of the diminishment of ovarian reserve. The prevailing dogma dictates that the primordial follicle reserve is fixed in utero and any insult reducing such reserve causes irreversible harm as oocyte regeneration is not possible in postnatal life. This dogma has been seriously challenged by several independent laboratories in recent years [4-5], even though some have expressed difference in opinion. While there has not been direct laboratory evidence in humans supporting or refuting the concept of germ cell renewal, our clinical and laboratory observations lend support to the existence of oocyte regeneration in human ovaries [6-7]. Ovarian cryopreservation is an experimental fertility preservation strategy which allows conservation of primordial follicle-rich ovarian tissue collected prior to gonadotoxic chemotherapy. After the completion of the cancer treatment and when fertility is desired, these tissues are thawed and transplanted back, enabling reversal of menopause. We have developed and performed first series of ovarian Commentary transplants in humans [8]. One of the ovarian transplantation techniques is transplantation of ovarian cortical strips under the skin [9]. In a cancer patient who became menopausal as a result of intense chemo-therapy, we observed that transplantation of previously frozen ovarian cortical strips under the abdominal skin resulted in immediate reversal of menopause and four consecutive pregnancies with three live births [7]. This appeared to be the result of the activation of the remaining menopausal ovary in response to the transplantation of undamaged ovary under the skin. We speculated that chemotherapy is likely to damage the ovarian germ cell niche, as our earlier work suggested [2], resulting in the inability of the ovary to regenerate new oocytes. We surmised that the transplanted ovary provides the necessary regenerative signals from its niche to the preexisting ovary through the circulation, enabling this chemotherapy-damaged ovary to reinitiate oocyte generation (Figure 1). Our clinical observations are in line with the parabiotic …