History

For many years, organ transplantation has been a medical and surgical challenge. Since the first kidney transplant in the early 1960’s, many scientists have been inspired to attempt transplantations of other vital organs such as the liver, heart, lung and pancreas. During that time, azathioprine (Imuran) and prednisone were the only available immunosuppressive agents. In 1980, the prognosis for transplanted organs became more favorable with the development of cyclosporine therapy. Safer and more easily tolerated immunosuppressive therapy has opened the doors for the transplant of non-vital organs such as the uterus.

In 1896 Knauer published the first study of ovarian transplantation and Grigor’ve that lead to the investigation of uterine auto-transplantation in 1918. Erslan, Hamernik and Hardy, in 1964 and 1966, were the first to perform an animal auto-transplantation of the uterus and subsequently deliver a pregnancy for that uterus (Erslan et al. 1966). With the availability of IVF in 1978, investigation of uterine transplantation was deferred (Confino et al. 1986). In 2000, a human uterine transplant was performed in Saudi Arabia by Dr. Wafa Fagee. Post-operatively, the patient had two spontaneous menstrual cycles, followed by amenorrhea; exploratory laparotomy confirmed uterine necrosis. Its mere attempt, however, raised many moral and ethical concerns.

Indications

Much of the animal research that has been investigated in the past have explored the feasibility of uterine auto transplantation and have neglected the role of uterine allo-transplantation as well as the influence of immunosuppressive therapy on fertility. Infertility and surrogacy, which also has been considered another alternative for infertility, have been subjected to legal, moral, ethical and religious restrains. This has then led for us as physicians to investigate cautiously the indications for human uterine transplants. The prime candidates for human uterine transplants are: (1) for those with a congenital absence the uterus (e.g. Mayer Rokitanksy Kuster Hauser Syndrome) (2) that have lost their uterus secondary to an obstetrical complication (e.g. post-partum hemorrhage) and (3) for those that have lost their uterus for benign causes (e.g. pelvic inflammatory disease, fibroid uterus, pelvic tuberculosis) or early invasive cervical or ovarian malignancies at an early age.

For some women not having a uterus may impose a state of emptiness and depression. By correcting this stigmata, the uterine transplant procedure may alleviate some of these emotional disturbances. While given the fact that the estimated incidence of Mullerian agenesis is approximately 1 in 4000 and understanding the different incurable causes of infertility, it is essential to provide other alternatives aside from surrogacy and adoption, in order to improve the quality of life for these selected patients.

Ethical and Religious issues

Several organ transplants are currently being performed to sustain viability of an individuals life however introducing the possibility of womb transplants have raised many moral and ethical issues since this organ is considered non-vital. Theoretically speaking the uterus may be considered a vital organ hence that its presence is required in order to sustain the life of a fetus. Another concern is the effect of immunosuppressive therapy on the fetus. Based on retrospective studies collected on patients with previous solid organ transplants, a slight increase in incidence of preterm delivery and small gestational pregnancies have been documented without any change in the incidence of birth defects.

Judaism, Christianity and Islam are considered the three prime religions. When discussing the issue of assisted reproductive technology, the Jewish people present their offer to the rabbi and invariably have no problem. The Christians present their desire to the priest and depending on the method of reproductive therapy, a blessing is granted. The Muslims have no problems with different forms of reproductive technologies with the exception of donor insemination. However patients with infertility will except any form of reproductive technology in order to obtain a pregnancy.

Discussion

Doctor Hugo A. Ramirez, an OB/GYN, moved to the United States from Bogota, Colombia in 1967 with the vision of introducing the uterine transplant procedure to the medical community. Through his years of investigative research and private practice he developed two doctors, Dr. Edwin and Doris Ramirez. The initial phases of their research were conducted on auto and allographs at Texas Tech University and New York Medical College. It was then continued in South America Colombia where more than 70 uterine transplants were performed on five animal models with a 94 % success rate in the ovine group (cats, dogs, pigs, sheep and goats). This project provides novel insight into the possibility of allo-transplantation. During the years of active research, the Ramirez family have explored different methods of revascularization of the transplanted organ, a concern for human subjects who may be eligible for allo-transplantation due to uterine agenesis.

As described, the first experiments were performed in cats, but the technical limitations imposed by the small feline reproductive organs and vessels prompted a search for a larger animal model. A canine model served as the avascular controls while ovine, cabras and porcine models explored the feasibility of uterine artery reanastomosis (the "vascular" group). The size of the porcine reproductive tract would have made them an ideal model but their high risk of malignant hyperthermia during anesthesia made the porcine model impractical. The preliminary study was therefore completed in goats and sheep. The cabra and ovine reproductive anatomy and endocrine function are similar to that of humans and they better tolerated the surgical and anesthetic procedures.

Current Investigation

Uterine transplant research is currently being investigated in California, Sweden, New York, London and Saudi Arabia. Previous and present studies have documented viability of uterine transplants on subprimates and primate species. Promising results have inclined the interest to investigate even further, the role of uterine transplants on fertility.

Conclusion

In order for human uterine transplants to be successful, surgical technique and teamwork are essential. By exploring the different alternatives for fertility such as in vitro fertilization, gamete intrafallopian tube transfer, intracytoplasmic sperm injection and surrogacy, the uterine transplant may be considered another alternative for infertility.

If you would like to learn more about uterine transplants, a live documentary can be viewed at the following link:

http://wrekk.net/vid/UT%20Doc%20256k.wmv

www.uterinetransplant.com

Edwin Ramirez, MD

Pioneer of Uterine Transplant Research

New York Medical College

Department of Obstetrics and Gynecology

Professor, University Autonoma of Guadalajara

Professor, International University of the Health Sciences

References

1. Bykow SG. Autotransplantation der Gebe-mutter in Hund. Monatschr Geburtsh Gynakol 76:186, 1927

2. Benjamin MM. “outline of veterinary clinical pathology.” Ames, Iowa State University Press 1961

3. Baird CL. Histologic studies of allografts of uterine tissue in rats. J Pathology 100:105,1970

4. Cohen BM, Morgenthal JC, Davey DA, Van Niekerk CH, Uys CJ, Botha MC, Du Toit E, Harrison VC Hickman R, Lotter F, Poole DM. “Completed pregnancy following vascularized heterotopic autotransplantation of the Fallopian tube in the ewe”. Int J Fertil. 1976:21 (3) : 153-8

5. Cohen BM. “Preliminary experience with vascularised Fallopian tube transplants in the human female”. Int J Fertil. 1976; 21 (3) :147-52.

6. E. Confino, M. Vermesh, W. Thomas and N. Gleicher. Non-vascular Transplantation of the Rabbit Uterus. Int J Gynecology,1986,24:321-325

7. Einer-Jensen N. Induction of ovulation by bis (p-acetoxyophenyl)-cyclohexylidenemethane (F6066) in the dog. Nord Vet Med 19:236,1967

8. Eraslan S, Hamernick R and Hardy JD. Replacement of uterus and ovaries in the dogs with successful pregnancy. Archives of surgery 92:9-12,1966

9. Martine RH. Ovarian transplantation. Surgical Gynecology and Obstetetrics 35:573,1922

10. Martine FH. Transplantation of ovaries. Surgical Gynecology and Obstetrics 7:7 1968

11. Mazer C and Israel SL. “Menstrual disorders and sterility.” New York, Hoerber,1951, p.362

12. Novak ER. “Textbook of gynecology.” Baltimore, Williams and Wilkins Co, 1970, p 549

13. R Racho El-Akouri, G Kurlberg, G Dindelegan, J Molne, A Wallin, M Brannstrom. Heterotopic uterine transplantation by vascular anastomosis in the mouse. Journal of Endocrinology (2002) 174, 157-166

14. Scott JR, Pitkin RM and Yannone ME. Transplantation of primate uterus. Surgery Gynecology and Obstetrics 133:414,1971

15. Tyler ET. “Sterility.” New York, McGraw-Hill Co, 1961

16. Wingate MB, Karasewich E, Windgate L, Lauchian S and Ray M. Experimental uterotubovarian homotransplantations in the dog. American Journal of Obstetrics and Gynecology 106:1171, 1970