Modern Trends in Reproductive Organ Transplantation Advances and Controversies

13 02 2009

To the Editor:

The highly erudite and learned review by Bedaiwy, Shahin and Falcone (1) has excellently addressed most of the issues regarding ovarian transplantation and oocyte preservation, but has omitted a few of the classic presentations related to tubal and/or tubo-ovarian transplantation.

The golden age of transplantation was from the mid 1960’s through the 1980’s, during which liver, heart, pancreatic, genital, ovarian and tubal transplants underwent major strategic and surgical progress (2). 

As indicated in the review (1), problems related to immunosuppresion remain an obstacle with respect to reproductive organ transplants.

Ovarian transplantation in the human was first performed by Raul Blanco et al in 1972 (3) and this work was presented at the 8th World Congress on Fertility and Sterility in Buenos Aires in 1974.  Tubo-ovarian transplantation was carried out by Zhordania and Gotsiridze (4) and Winston and McClure Browne in 1974 (5).  Replacement of the uterus together with both fallopian tubes and ovaries was documented by Zhordania and Gotsiridze (4) and multiple other authors. 

Vaginal transplantation from mother to daughter was performed in the human female by Papanicolaou et al in 1971 (6). 

Our work describing the strategy and techniques for vascularized fallopian tube transplantation was published from 1974 onward (7-11).

The important issue relevant to this current major review (1) was our documentation related to vascular anastomosis of vessels subject to major spasm and thrombosis, e.g. uterine arteries, and this would also apply to vessel size discrepancy.

Terminal side-to-side anastomosis, not reviewed in the current article, had the highest patency rate.  One hundred percent patency was observed in vascularized fallopian tube transplants using terminal side-to-side technique in sheep (7-11). 

When reporting a high incidence of vascular thrombosis in ewes (1, 12-14) it is unfortunate that the researchers completing this work were not aware of our data.  A high incidence of vascular patency obtained by a terminal side-to-side anastomosis would have afforded more realistic outcomes regarding the amount of ovarian preservation possible.

We also documented the need to have maximal safety, so we preferred ovarian vein end-to-side anastomosis (avoiding the vena cava) to minimize risk should removal of the transplant be necessary due to infection or rejection.

The technique of vascularized fallopian tubal transplantation in the human was also described and our initial experience was published (8).

A further observation was our recording preservation of the transplant organ after its excision with cold pulsatile perfusion of oxygenated culture medium prior to its transfer to the recipient (8).  It is of note that a similar technique was recently documented as the most efficacious for preservation of renal tissue while in transit, before transplantation to the recipient (15).

Omission of these reproductive organ transplant articles reflects a modern trend in our medical literature where authors in good faith but probable ignorance, fail to thoroughly review the classic original literature in a particular field. 

There were major developments in medicine prior to the 1990’s and the practice of omitting early literature should be carefully and critically scrutinized by all editors. 

I trust that these viewpoints will constructively contribute to our further development of ovarian and reproductive organ transplant methods in the future.

Brian M. Cohen, M.B.Ch.B., M.D.
Department of Obstetrics and Gynecology
The University of Texas Southwestern Medical Center at Dallas

Cohen Center
Dallas, TX

 References
1. Bedaiwy M, Shahin A, Falcone T. Reproductive organ transplantation: advances and controversies. Fertil Steril 2008;90:2031-55.

2. Najarian JS, Simmons RL. Transplantation. Philadelphia: Lea & Febiger, 1972.

3. Blanco R, Dominguez M, Bur GE, Galimberti D, Castillo Odena T, Pairola R, et al. (The transplant of ovary in the human being; first case with later gestation.) Trab. Pub. Rev. soc. Obstet. Ginecol. Buenos Aires 1972; L1, 295.

4. Zhordania IF, Gotsiridze OA. Vital activity of the excised uterus and its appendages after their autotranplantation into omentum. Acta Chir Plast, 1964;6:23-32.

5. Winston RML, McClure Browne JC. Pregnancy following autograph transplantation of fallopian tube and ovary in the rabbit. Lancet 1974; 2(7879):494-5.

6. Papanicoloau NA. (Transplantation of the vagina from mother to the daughter. Behavior of the transplant tissue.) Minerva Ginecol, 1972 May;24(7):356-62.

7. Cohen B. Preliminary experience with vascularized fallopian tube transplants in the human female. Int J Fertil 21: 3, 1976.

8. Cohen B. Vascularized transplantation of the fallopian tube in the human female-A proposed surgical technique. Int J Fertil 21: 3, 1976.

9. Cohen B, Morgenthal D, Davey D, Van Niekerk C, Uys C, Botha M, Du Toit E, Harrison V, Hickman R, Lotter F, Poole D. Completed pregnancy following vascularized heterotopic autotransplantation of the fallopian tube in the ewe. Int J Fertil 21: 3, 1976.

10. Cohen B. The strategy of vascularised transplantation of the fallopian tube. S Af Med J. 48, 2097 (1974).

11. Cohen B, Morgenthal D, Davey D, Van Niekerk C, Uys C, Botha M, Du Toit E, Harrison V, Hickman R, Lotter F, Poole D. Pregnancy after autotransplantation of the fallopian tube in the ewe. S. Afr.med. J. 50, 1179 (1976).

12. Cohen BM. (1975). The development of a technique for vascularized transplantation of the fallopian tube in the pig with reference to its application the human female. Postgraduate doctoral thesis, University of Cape Town, Cape Town, Republic of South Africa.

13. Bedaiwy MA, Jeremias E, Gurunluoglu R, Hussein MR, Siemianow M, Biscotti C, Falcone T. Restoration of ovarian function after autotransplantation of intact frozen-thawed sheep ovaries with microvascular anastomosis. Fertil Steril 2003;79:594-602

14. Imhif M, Bergmeister H, Lipovac M, Rudas M, Hofstetter G, Huber J. Orthotopic microvascular re-anastomosis of whole cryopreserved ovine ovaries resulting in pregnancy and live birth. Fertil Steril 2006;85:1208-15.

15. Moers C, Smits J, Maathuis MHJ, Treckmann J, van Gelder F, Napieralski BP, et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med 2009;360:7-19.

Published online in Fertility and Sterility doi: 10.1016/j.fertnstert.2009.02.044

The Authors Respond:

We would like to thank Dr. Cohen for his interest in our manuscript (1). We appreciate very much the historical insight of Dr Cohen by bringing to the attention of the readers his thorough and extensive early work on tubal transplantation conducted mainly in the seventies in the pre-IVF era.

Tubal transplantation was thought of as a possible alternative for patients with severely damaged tubes. Few human case reports were recorded including the two patients reported by Dr Cohen (2).  Unfortunately, neither mechanical nor functional patency of the transplanted tubes was reported. Both tubes were removed shortly after transplantation due to immunological rejection as well as febrile and infectious morbidities.The pathology report showed that the excised transplant consisted of an irregular mass of tissue no longer recognizable as a fallopian tube with almost total necrosis (2). This demonstrates the critical importance discussed in our review of immuno-suppressive medication for allogeneic transplants.

Vaginal transplantation was attempted in humans.  The immune rejection of skin tissue is usually even more robust than solid organs. Consequently out of all reproductive organs, we are left with the ovarian and the uterine transplantation which were the focus of our review. Our perspective for Modern Trends section of Fertility and Sterility is to provide the readers with an up-to-date review of modern innovative experimental and clinical ideas. Reviewing the evolutionary history of reproductive organ transplantation, including techniques that no longer practiced, was beyond the objectives of our review.

Regarding the vascular anastomosis technique, the authors reported that they have a 100% patency rate using terminal side-to-side anastomosis. The histopathology of both human transplants where they adopted the side-to-side anastomosis technique demonstrated near complete necrosis and thrombosis of the anastomsed vessels (2). It could be a 100% patency rate in their animal experiments where autotransplantation was adopted, but indeed it was not the case in the 2 human cases reported by the author.

In modern microvascular literature several methods are used to establish an appropriate anastomosis. Discrepancies in the cut  end diameters of blood vessels have been managed by many geometrical methods in order to reduce the risk of thrombosis (3, 4). Minor discrepancies less than 1:1.5 are usually dealt with by dilatation with the use of a jeweller’s forceps (5). Discrepancies exceeding 1:1.5 are usually dealt with using the oblique cut, fish-mouth cut, or end-to-side anastomosis (5). When a major discrepancy is anticipated and the upstream donor vessel is smaller than the recipient one, a sleeve anastomosis can be performed (4). Other geometrical designs (oblique cut or Y cut), devices, glues or adhesives and laser-assisted anastomosis are to be considered according the surgeon’s experience (3, 4).

In conclusion, after reviewing the microvascular surgery literature, end-to-side is not associated with higher patency rates then end-to-end and side-to-side is almost never used in microsurgery except when performing arteriovenous fistula for hemodialysis.

Mohamed A Bedaiwy MD, PhD
Tommaso Falcone MD
Department of Gynecology and Obstetrics
University Hospitals Case Medical Center
and Cleveland Clinic
Cleveland, Ohio, USA.

References:
1. Bedaiwy MA, Shahin AY, Falcone T. Reproductive organ transplantation: advances and controversies. Fertil Steril.;90(6):2031-55.

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

3. Lopez-Monjardin H, de la Pena-Salcedo JA 2000 Techniques for management of size discrepancies in microvascular anastomosis. Microsurgery 20, 162–6.

4. de la Pena-Salcedo JA, Cuesy C, Lopez-Monjardin H 2000 Experimental microvascular sleeve anastomosis in size discrepancy vessels. Microsurgery 20, 173–5.

5. Cakir B, Akan M, Akoz T 2003 [The management of size discrepancies in microvascular anastomoses]. Acta Orthopaedica et Traumatologica Turnica 37, 379–85.

Published online in Fertility and Sterility doi: 10.1016/j.fertnstert.2009.02.045

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One response

16 03 2009
Brian M. Cohen, M.B.Ch.B., M.D.

March 16, 2009

Re: The author’s response to Letter-to-the-Editor Modern trends in reproductive organ transplantation advances and controversies

The author’s response utilizes the original article to confuse the readership regarding the main issues related to transplantation of the fallopian tube with uterine arterial anastomosis.

The hallmark of rejection is the entry of macrophages and histiocytes into the transplanted tissue, simultaneously releasing cytokines, which participate in total and mass thrombosis of the transplanted organ. This effectively isolates the foreign tissue from the recipient host.

Reference to the original publication indicates that the transplanted tube had cornual patency and thus the tubal anastomosis was mechanically successful.

Both transplanted tubes manifested the classic features of rejection including cellular infiltration and the accompanying thrombosis proof of prior vascular patency to facilitate the rejection response.

The one oviduct was removed three months after the transplant procedure once conception had not occurred and its histology was consistent with chronic rejection.

The second fallopian tube was removed days after transplantation and the organ was extremely enlarged (more than five times its original size) with all the classical histological features of an accelerated rejection response, facilitated by its patent arterial anastomosis.

At the site of the uterine artery, prior prospective vascular head to head studies comparing end-to-end and terminal side-to-side anastomosis in 44 procedures proved conclusively that the latter was the most efficient method of achieving vascular patency of uterine arteries (1). This original technique, when published, fascinated many vascular surgeons as it was a new method and the data stands for itself.

I humbly suggest that the readership review the complete original article and make their own scientific judgment and conclusions regarding vascular surgical techniques at the site of the uterine artery.

Brian M. Cohen, M.B.Ch.B., M.D.
Clinical Professor, University of Texas Southwestern Medical Center at Dallas

References
1. Cohen BM. The development of a technique for vascularized ransplantation of the fallopian tube in the pig with reference to its application in the human female (doctoral thesis). Cape Town, South Africa: University of Cape Town, 1975.

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