To the Editor:
It was encouraging to see that our article on uterine transplantation in nonhuman primates was discussed on the editorial page. We believe that it is important for attainment of clinical application to validate uterine transplantation in primate models. We agree with many of the comments made by Dr. Tzakis (1). These comments accurately identify challenges specific to the background of uterine transplantation experiments in primates.
First, uterine transplantation is conducted for improved quality of life, which differs from transplantation of organs for life support. Organ transplantation started decades ago; however, studies of the uterus were rare because uterus dysfunction is not life-threatening. However, the bioethical view has changed over time and with technology development, the number of uterine cancer survivors has increased, with a corresponding need for improved postoperative quality of life. Consequently, uterine transplantation with the goal of delivery in patients with uterine factor infertility is of increasing importance. It is clear that such patients cannot deliver a child without intervention, and many also lose female identity or may experience marital problems, resulting in psychological and social distress. Uterine transplantation has the potential to improve quality of life by providing the potential for pregnancy and delivery with assisted reproductive technology (ART).
Second, the safety and effectiveness of surgical procedures for uterine transplantation have been validated in various animal models. For example, we have achieved pregnancy and delivery after uterine autograft in a cynomolgus monkey (2). However, pregnancy or delivery by uterine allograft in primates has yet to be attained and further studies in this area are needed.
Third, we very much agree with Dr. Tzakis’s comment concerning the limitation of experimental controls in basic studies in nonhuman primates. These animals are anatomically and physiologically similar to humans; therefore, they are an appropriate model for planning the clinical application of uterine transplantation. However, there are still difficulties in postoperative control and ART, and limitations in the use of these animals for experiments. Postoperative control of blood concentration of immunosuppressive agents is important due to effects on graft survival, but it is difficult to administer these agents orally in animals as scheduled, and delivery through enteral feeding is problematic because of marked anorexia after invasive surgery. Intravenous administration is simple in humans, but difficult to control in animal models. Intramuscular injection is similarly problematic. Difficulties in infusion also cause marked postoperative weight loss that cannot be recovered by supplementation with oral nutrients alone in many animals.
A further problem is that ART is essential after uterine transplantation in humans, but this aspect of the procedure is not sufficiently established in nonhuman primates. A group in Sweden used baboons (3), but sperm counts in males were extremely low. We used cynomolgus monkeys, but could not conduct transvaginal embryo transfer due to cervical bending and tortuosity that differed from humans. Technology to conduct transtubal embryo transfer in cynomolgus monkeys has gradually been developed; however, abdominal adhesion is severe after uterine transplantation and the fallopian tube is often obstructed.
Finally, the costs of experiments using primates are a major problem, and we agree with the opinion that performance of a study with inclusion of many animals is difficult. There are also limitations from the perspective of animal welfare and other challenges specific to primates, in comparison with small animals.
In summary, further validation of uterine transplantation is needed in primate models, and the outcomes will be important for successful clinical application in humans. However, these studies should be conducted with the recognition that primate models have specific problems and limitations, and that the results may not always correspond directly to those in humans. The current performance of clinical applications of uterine transplantation in humans is an exciting development. The outcomes of these procedures are likely to be improved by accumulation of data from further animal studies, including primates.
Iori Kisu, M.D., Ph.D., Kouji Banno, M.D., Ph.D., Daisuke Aoki, M.D., Ph.D.,
Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan
1. Tzakis AG. Nonhuman primates as models for transplantation of the uterus. Fertil Steril 2013.
2. Mihara M, Kisu I, Hara H, Iida T, Araki J, Shim T, et al. Uterine autotransplantation in cynomolgus macaques: the first case of pregnancy and delivery. Hum Reprod 2012;27:2332–40.
3. Johannesson L, Enskog A, Dahm-Kähler P, Hanafy A, Chai DC, Mwenda JM, et al. Uterus transplantation in a nonhuman primate: long-term follow-up after autologous transplantation. Hum Reprod 2012;27:1640–8.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2013.04.011