Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue a review of 60 cases of reimplantation

Capsule:
A review of 60 cases of frozen-thawed ovarian tissue reimplantation is presented. Cryopreservation of ovarian tissue is the only option available for prepubertal girls and for women who cannot delay the start of chemotherapy.

Authors:
Jacques Donnez, M.D., Ph.D., Marie-Madeleine Dolmans, M.D., Ph.D., Antonio Pellicer, M.D., Ph.D., Cesar Diaz-Garcia, Maria Sanchez Serrano, M.D., K.T. Schmidt, M.D., E. Ernst, M.D., Valérie Luyckx, M.D., Claus Yding Andersen, M.D.Sc.

Volume 99, Issue 6, Pages 1503-1513, May 2013

Abstract:

Aggressive chemotherapy and radiotherapy, and bone marrow transplantation (BMT), can cure >90% of girls and young women affected by disorders requiring such treatment. However, the ovaries are very sensitive to cytotoxic drugs, especially to alkylating agents. Several options are currently available to preserve fertility in cancer patients. This present review reports the results of 60 orthotopic reimplantations of cryopreserved ovarian tissue as well as the 24 live births so far reported in the literature. Restoration of ovarian activity occurred in nearly all cases. Among the 60 patients, 11 were pregnant and 6 of them already delivered 12 healthy babies. In the future, we should pay attention: 1) to improve the freezing techniques; 2) to favor the “vascular bed” before reimplantation, in order to increase the pregnancy rate. On the other hand, freezing of ovarian tissue may be combined with removal, via puncture, of small antral follicles making it possible to freeze ovarian tissue and isolate immature oocytes.

  • mark winstanley

    This is great work and knowing the denominator makes this so much more informative. I see that there has been pubertal induction with pre-pubertal stored tissue but has anyone as yet had successful pregnancy with frozen pre pubertal ovarian tissue? if so how many of the 24? thanks for your help with this.

  • Dr Sherman Silber

    This is an important review on ovary freezing and transplantation for preserving fertility for cancer patients, written by three institutions that we collaborate with. But i honestly do NOT know why these three did not include our institution or others in this review, which would have made it much stronger. In fact there are NOT 24 documented live births from this technique, but rather 29 using frozen tissue and 12 more using fresh ovarian tissue, for a total of 41 live births from transplanted ovarian cortical tissue. THESE OMISSIONS ARE MORE IMPORTANT THAN IT MAY SOUND IN THAT WORLDWIDE IT SHOULD BECOME CLEAR THAT THIS IS NOT AN “EXPERIMENTAL” PROCEDURE as ASRM has labelled it. In fact there may be zero to only a few live births in cancer patients from frozen eggs, but 31 documented live births for cancer patients using ovarian tissue.

    So it was a chance missed for these authors to not include Piver, and Revel, and Meirow, Kovacs, and myself (Silber) in this paper, which would show worldwide a large group of programs with success far greater than that documented yet for freezing eggs for cancer patients. It is crucial that this no longer be labelled as “experimental” for cancer patients, so as to get insurance company reimbursement in the United States. Yet they never included three of my recent papers which included 11 babies from fresh ovary transplant (two cancer cases), and three babies from frozen ovary transplant ( two cancer cases and one POF), for a total of 4 more healthy babies, nor the three cases of Piver, nor the new case of Kovacs, nor the new cases from Revel and colleagues and Meirow and colleagues from Israel recently reported.

    THE MAIN POINT IS THAT ASRM MUST NO LONGER CONSIDER OVARY FREEZING TO PRESERVE FERTILITY FOR CANCER PATIENTS AS “EXPERIMENTAL”, if they are willing not consider egg freezing for cancer patients as “not experimental”.

    I refer the authors to our latest papers they did not reference:

    SJ Silber, Molecular Human Reproduction, 18:59-67, 2012.
    SJSilber and N Barbey, Biochimica et Biophysica Acta, 1822 (2012) 1981-1966.
    CAndersen, S Silber, et al., RBM Online(2012) 25, 128-132.
    SJ Silber et al, Abstract ASRM October 23, 2012, p.S35

    Dr Sherman Silber
    224 Woods Mill Rd
    St Louis, Missouri 63017
    US

    • Jacques Donnez

      I read with interest the remarks of Sherman Silber and I am happy to answer:

      1) The view and review section is focused on fertility preservation methods, including embryo, oocyte and ovarian tissue.

      2) The present manuscript is devoted to ovarian tissue cryopreservation and to thawing and grafting, analyzing the data on restoration of ovarian activity and live births. Thus, the goal was clearly to include only the cases of reimplantation of frozen tissue and not the cases of fresh tissue reimplantation. Otherwise, of course,I had also included the 3 life births obtained in my department after fresh tissue reimplantation.

      3) We have included 24 live births because these 24 live births were published and thus the manuscripts related to them was peer-reviewed (and I hope that Sherman Silber will agree with that). Indeed, in a scientific journal like Fertility and Sterility, all submitted data should be controlled and there is no question to increase the number of live births, simply by calling different doctors or centers and asking them “How many live births do you have”. I clearly write in the manuscript 24 live births and 4 ongoing pregnancies. To my knowledge,this is the reality of the published literature.

      4) I asked to another team (that I know they have more than 10 transplantations of frozen tissue) but I never received the data.

      5) The most important question (that we are frequently asked to answer during the meetings on cryo) is “Do you know the denominator (the total number of transplantation) in order to know the live births rate per transplantation?”. As a registrar seems to be difficult to establish (for many reasons), we decided to collect the data from 3 european centers, having more than 10 cases of reimplantation of cryopreserved ovarian tissue.

      Indeed, all information obtained from these 3 centers allow us to

      clearly define a success rate per transplantation. After these remarks, I would agree with Sherman Silber that it is time not to consider anymore ovarian tissue freezing as experimental.

      • Dr Sherman Silber

        our disagreements are minor. what is clear is that the authors all agree
        that ovary tissue freezing for cancer patients should no longer be considered “experimental”. but i would add that, if you look at the results of revel in israel, as well as of meirow and dor in israel, plus our results in st louis (which have been published but not referred to), the success rate is very high for pregnancy and live birth, as in all three of our institutions, more than half of the frozen transplants have resulted in live births, in tel aviv, in jerusalem, and in st louis.

  • Kutluk oktay

    This review by Donnez et al shows us that the true efficiency of ovarian freezing and transplantation is still unknown. Considering that many failures are not being reported and some of the livebirths might have occurred due to the follicular activity from the remaining ovary, actual success rates are likely to be lower. Research should continue to find the ways to enhance revascularization afetr ovarian transplantation. As we recently reported S1P might be one of the agents that may offer improvement in that area. Please see this publication http://www.ncbi.nlm.nih.gov/pubmed/21559342

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