Reply: Ethical issues surrounding the crypreservation of human oocytes

LETTERS TO THE EDITOR Paul G. McDonough, M.D. Associate Editor Ethical issues surrounding the cryopreservation of human oocytes To the Editor: In response to the article by Drs. de Melo-Martin and Cholst, we support and oblige the authors’ request for ethically performed oocyte cryopreservation studies (1). The authors conclude that the most ethical way to perform the research necessary to evaluate this new technology, oocyte cryopreservation, would be through the use of donor oocytes and recipient women with infertility. We completely agree with their recommendations, as evidenced by the fact that we published an article elsewhere that used such a protocol (2). Our analysis of four oocyte cryopreservation cases using donor oocytes and recipient couples was performed after years of intense debate within our center about the ethical and possible medical concerns with this type of human study. Only after applying for and receiving institutional review board approval for a prospective study that used oocyte donors and IVF patient recipients; after spending years on laboratory research and development to technically master the procedures of oocyte cryopreservation and thawing; and finally, after appropriately counseling and providing informed consent to the patients involved, did we at last, with great caution, undertake this study. In the de Melo-Martin article, the authors state, ‘‘current (pregnancy rates) still appear to be lower than those seen with standard IVF procedures (1).’’ They cite Borini et al. (3) for the success rates with this new procedure; however, that study was severely restricted by Italian laws that only an extremely limited number of oocytes and embryos may be fertilized and transferred, which clearly reduces the true potential success that could be achieved with this technique. Although our series was small, the results were dramatic. We demonstrated that three of four patients conceived and delivered after using frozen and thawed donor oocytes, which is comparable to the pregnancy rate that we found in our fresh-oocyte donor program. In addition, our implantation rate of 26% is five times greater than that in the results of Borini et al. (3), demonstrating that both the number of embryos transferred and the quality of the embryos created after oocyte cryopreservation and thaw resulted in our high success rate. Finally, the authors suggest, ‘‘Also important to consider when designing research protocols for oocyte cryopreservation is the issue of costs. Because oocyte cryopreservation is still an investigational procedure, and until a center achieves some degree of success, it can be argued that the costs of the procedure should not be charged to the patient.’’ 1016

In our study, the recipient did not pay donor compensation or for health screening or cycle medications that were associated with the donor. Our study demonstrated that it is indeed possible to perform oocyte cryopreservation research in an ethical, institutional review board–controlled, donor egg model. We published our methods and findings in this respected peer-reviewed journal to provide the reproductive community with the knowledge that we gained. Human oocyte cryopreservation, when performed in a safe and controlled manner, can be an effective technique that can be applied in clinical situations and can show high oocyte survival and clinical pregnancy rates, opening the door for this technique to be used for women choosing to preserve their fertility. Jason Barritt, Ph.D. Martha Luna, M.D. Marlena Duke, M.Sc. Alan Copperman, M.D. Mount Sinai School of Medicine Reproductive Medicine Associates of New York New York, New York June 29, 2007 REFERENCES 1. de Melo-Martin I, Cholst IN. Researching human oocyte cryopreservation: ethical issues. Fertil Steril. Published online May 16, 2007. 2. Barritt J, Luna M, Duke M, Grunfeld L, Mukherjee T, Sandler B, et al. Report of four donor-recipient oocyte cryopreservation cycles resulting in high pregnancy and implantation rates. Fertil Steril 2007;87:189. e13–7. 3. Borini A, Sciajno R, Bianchi V, Sereni E, Flamigni C, Coticchio G. Clinical outcome of oocyte cryopreservation after slow cooling with a protocol utilizing a high sucrose concentration. Hum Reprod 2006;21:512–7.

doi:10.1016/j.fertnstert.2007.07.1365 Reply of the Authors: We thank Drs. Barritt, Luna, Duke, and Cooperman for their response to our discussion of some of the ethical issues encountered in researching human oocyte cryopreservation (1). Our discussion highlighted many of the pitfalls involved in such investigation and suggested possible ways to conduct such research ethically. Because our main intention in writing the article was to use the issues raised by this experimental procedure as a way to broaden the conversation around the complex issue of informed consent, we are happy to see such a conversation taking place. Our intent was not to provide a set of recommendations. Also, although the Barritt et al. (1) work was published after the submission of our

Fertility and Sterility Vol. 88, No. 4, October 2007 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc.

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article (and we therefore were unable to reference their study), we are pleased to see that their group was attentive to some of the ethical problems that are raised when subjects are recruited for oocyte cryopreservation research studies (2). We are, however, surprised that the correspondents take issue with our statement that ‘‘current (pregnancy rates) still appear to be lower than those seen with standard IVF procedures,’’ on the basis that 75% (3 of 4) of their subjects conceived. These certainly are encouraging data, but we caution against the overenthusiastic use of small series to generalize about outcomes. In our article, we cite 10 studies of outcomes (references 18–27), as well as a review of the literature (reference 32). Taken together, and adding the excellent recent review by Jain and Paulson (3), these studies suggest that there still is considerable work to be done before we can consider this medical procedure comparable to ones that presently are available, and thus, one that can be offered confidently to patients, both for medical indications as well as possibly for nonmedical ones. As we point out in our article, overenthusiastic responses to clinical advances specifically may be related to some of the difficulties in evaluating new medical procedures and the resulting obstacles to obtaining informed consent from research participants. Inmaculada de Melo-Martin, Ph.D. Ina N. Cholst, M.D. Weill Cornell Medical College New York, New York July 17, 2007 REFERENCES 1. de Melo-Martin I, Cholst IN. Researching human oocyte cryopreservation: ethical issues. Fertil Steril. Published online May 16, 2007. 2. Barritt J, Luna M, Duke M, Grunfeld L, Mukherjee T, Sandler B, et al. Report of four donor-recipient oocyte cryopreservation cycles resulting in high pregnancy and implantation rates. Fertil Steril 2007;87:189. e13–7. 3. Jain JK, Paulson RJ. Oocyte cryopreservation. Fertil Steril 2006;86 (Suppl 4):1037–46.

doi:10.1016/j.fertnstert.2007.07.1366

An expert forum for the histology of endometriomas To the Editor: We read with interest the article by Muzii et al. (1) regarding the histologic analysis of endometriomas. However, we do not agree with the conclusions reached in that study regarding pathogenesis of endometriotic cysts. Because the authors have made important clinical recommendations on the basis of their findings, we would like to express our concerns with certain aspects of their methodology. Since we first reported on the laparoscopic management of severe endometriosis more than 2 decades ago, there has been Fertility and Sterility

a welcome burgeoning of clinical studies related to endometriosis (2). On the basis of our research and clinical experience, we have established a classification method for endometriomas. Although this classification has been referred to by Muzii et al. (1), it appears that they misunderstood some of our assumptions. In brief, we classify the endometriomas into two types: primary, or type I, endometriomas, which originate from endometriotic lesions that adhere to the ovary, bleed inside, and expand; and secondary, or type II, endometriomas, which are what Sampson originally referred to (3) and which originate from functional cysts that were invaded by plaques of endometriosis that bleed inside the cyst. Type I endometriomas usually are <5 cm in size, contain a dark fluid, and have capsules that are difficult to remove because they are associated with dense fibrosis and adhesions. Histopathological examination always shows endometrial glands and stroma in such cases. As for type II endometriomas, we have shown elsewhere that the functional wall of the cyst may gradually change to an endometrioma (4). It appears that the present study may have been affected to some extent by a selection bias, because all of the cases included were either type I or late-stage type II. Functional cyst-related endometriomas are diagnosed most clearly in their formative stages, whereas ovarian endometriomas of >3 cm were included in the present trial. Furthermore, the relatively small number of cases (n ¼ 59) investigated in the present study limits the ability of the investigators to reach a conclusive observation in regard to the controversial pathogenesis of endometriomas. Muzii et al. (1) note that the purpose of their study was to thoroughly examine the endometrioma wall to assess the presence, extent, and depth of penetration of endometriosis in the cyst capsule. However, it is recognized that ovarian cystectomy by itself may preclude complete evaluation of the ovary. It appears that only a study in which oophorectomy specimens were included would allow for more conclusive observations. Admittedly, in the literature, only a few studies report in detail the histologic nature of the endometrioma wall. In our article, we noted that the capsule of endometriomas could be up to 4 to 5 mm in thickness, so it must be removed to decrease the chances of recurrence (3). In the present study, the mean value of maximal depth of endometriosis penetration in the endometrioma wall was merely 0.6 mm. Yet Stratton et al. (5) reported in their study that endometriomas deeper than 10 mm were always histologically confirmed as endometriosis. This wide variability in the depth of invasion of endometriosis into the cyst wall may often be the explanation for the ultimate success of cystectomy. Supporting what we and other colleagues reported in 1986 (2), on the basis of histopathological findings, the latest systematic review of the Cochrane Database concluded that excisional surgery for endometriomata provides for a more favorable outcome than does 1017