Progress, history and promise of ovarian cryopreservation and transplantation for pediatric cancer patients.

Ovarian cryopreservation followed by transplantation is one of the potential ways fertility can be preserved and endocrine function restored in women who are at risk for ovarian failure, early menopause, or loss of fertility. While much of the progress in this area has occurred in the past couple of decades, the concept of transplantation of reproductive organs has been present since the nineteenth century. The first account of ovarian grafting was published in 1863 in a thesis by Paul Bert. Results were disappointing, hence the loss of interest over the next 30 years. In 1895, New York surgeon Robert Morris performed the first human ovarian implant in a woman with ovarian failure who reportedly became pregnant post-implant, though the pregnancy ended in a spontaneous abortion. Further experiments in ovarian grafting resulted in pregnancy in rabbits, dogs, and sheep from 1895 to 1899. However, because of the low success rate and limited clinical applicability of fresh ovary transplantation at that time, interest in this field waned [see review in 1]. The first attempts to cryopreserve ovarian tissue from rodents in the 1950s were largely unsuccessful, with only a 5% follicle survival rate due to several factors, including lack of effective cryoprotectants, automated cryopreservation machines, and optimized cryopreservation protocols [2–4]. By the 1970s, more effective cryoprotectants such as propanediol, ethylene glycol, and DMSO became available [5]. Slow cooling protocols were subsequently developed and successfully applied to ovarian tissue [6,7]. These developments resulted in restoration of fertility in up to 86% of rodents by the 1990s [8–12]. Despite these advances, doubt remained as to the applicability of these methods in humans since the rodent ovary is different from the bulkier, more fibrous human ovary with characteristically widely dispersed primordial follicles. Encouraging findings came in 1994, when Gosden demonstrated that ovarian cortical strips from sheep were able to survive cryopreservation and revascularize upon transplantation [8,13]. This was a significant step forward, as the sheep ovary is more similar to that of humans. By 1999, Baird showed that ovarian function was maintained for a limited though long-term (nearly 2 years) period in autotransplanted sheep [14]. Transplantation of the whole ovary after cryopreservation resulted in even longer-term function of more than 36 months [15]. In 2004, Lee reported the first live birth after heterotopic transplantation of fresh autologous ovarian tissue in the monkey [16]. There is less