Preservation of Reproductive Function Before Therapy for Cancer: New Options Involving Sperm and Ovary Cryopreservation
Editorial: "A New Perspective"
Michael S. Opsahl, M.D., Edward F. Fugger, Ph.D., Richard J. Sherins, M.D., and Joseph D Schulman, M.D.
Reprinted from The Cancer Journal from Scientific American. Copyright (c) 1997 Scientific American. All rights reserved.
In the past 3 years, the introduction of two new technologies has revolutionized the opportunities to preserve reproductive options for both men and women who are diagnosed with cancer. These involve the use of in vitro fertilization (IVF) with intracytoplasmic sperm injection (ICSI) after semen cryopreservation for men, and autotransplantation of gonadal tissue after ovarian tissue cryopreservation in women. Improved survival rates in cancer victims bring new awareness of and interest in quality-of-life issues such as reproduction. Broadening awareness of these options in the oncology community is the primary purpose of this editorial.
ICSI AFTER SPERM CRYOPRESERVATION
Semen freezing with appropriate cryoprotectants prior to initiating cancer therapies likely to destroy future sperm production has been utilized for some years. As conventionally provided, however, this strategy has several limitations. Semen of some men does not cryopreserve well (Genetics & IVF Institute, unpublished data), and the reduction or near absence of sperm survival in thawed specimens can be a significant limitation on subsequent pregnancy attainment by intrauterine insemination (IUI) or conventional IVF. This may be a particular problem for men newly diagnosed with lymphoma or testicular cancer whose semen frequently has poor quality prior to the institution of chemotherapy, radiation, or genital surgery (1). To provide an adequate reserve of samples for future use, semen is usually collected over a period of 1 to 2 weeks. Delays of this magnitude before initiation of cancer therapy are often considered undesirable, so it is common to have very few semen specimens stored before treatment begins. The reduced number of inseminations that can be undertaken with limited stored semen, and the frequently marginal quality of the specimens, contribute to enormous stress and, in many cases, later reproductive failure for affected couples.
The advent of ICSI has markedly enhanced the ability to preserve reproductive options for many men with newly diagnosed cancer. ICSI is a variation of IVF in which a single sperm is microinjected into each egg obtained from the woman after stimulation of her ovaries with godadotropins and transvaginal, nonsurgical, ultrasound-guided egg retrieval. ICSI was developed in Brussels in 1992 by Van Steirteghem, Palermo, and coworkers (2). It has proven to be an extraordinarily useful technology for treatment of severe male infertility (3), and thousands of pregnancies worldwide have now been achieved (4). So powerful is this option that couples have actually been able to attain pregnancies when the husband's sperm production was so abnormal that fewer than 10 living sperm could be identified for use in microinjection! With a woman in her early to mid thirties, pregnancy rates achieved by leading ICSI teams approximate 30% per treatment cycle but can be higher in younger women producing larger numbers of embryos. There have also been many ICSI pregnancies in women in their early forties (3,4). However, if the cancer patient's female partner is in her mid forties or beyond, oocyte factors usually will require the use of oocyte donation (Donor Egg IVF) for pregnancy attainment with ICSI (5). Remarkably, pregnancy rates with ICSI therapy are virtually independent of the degree of semen abnormalities, freeze/thaw quality of the semen, and number of available sperm (3,6).
The implications of ICSI for men with newly diagnosed cancer are dramatic. There is almost always enough time to obtain at least one semen sample before starting treatment for malignancy. A single ejaculate, even if of poor quality, will usually contain at least a few million living sperm. A cryobank experienced at working with sperm for ICSI can take a single ejaculate, add cryoprotectant, and freeze the specimen in a large number of very small aliquots containing a few thousand sperm each. Usually, only one of these many aliquots is needed to provide enough living sperm for one ICSI cycle. Thus, a single ejaculate will usually provide sufficient sperm for any number of future attempts at ICSI. Of course, if time before therapy permits it, additional semen samples can be frozen so that pregnancy can be attempted initially with intrauterine inseminations, with ICSI as a backup option if this simpler strategy fails.
In a subset of male patients, ejaculatory or erectile dysfunction may occur as a result of extensive pelvic and/or retroperitoneal surgery (from testicular, bladder, and prostate cancer), which interrupts neurological control of genital function. Sperm production is preserved in many such men, but they cannot mechanically deliver sperm from the epididymal reservoir to an ejaculate. With ICSI, it is now possible to achieve high fertilization and pregnancy rates using sperm obtained directly from the epididymis or testis via surgical extraction (6) and recently by non-surgical needle aspiration (7) under sedation in an outpatient setting.
ICSI now provides an important reason to encourage semen cryopreservation of at least one ejaculate before initiating cancer treatment in nearly every male whose future reproductive function is likely to deteriorate afterward. This has great and obvious value for men who indicate a clear desire to have children in the future.
Cryopreservation of semen for possible future ICSI is so simple and inexpensive that it may also be worth considering by males with less clear-cut future reproductive goals, including men who have apparently completed their families and are planning vasectomy; their desires may change, and factors such as future remarriage or even the death of a child cannot be excluded.
AUTOTRANSPLANTATION OF CRYOPRESERVED OVARIAN SLICES
Women of reproductive age with newly diagnosed cancer may suffer irremediable oocyte destruction from many therapeutic regimens. In the past, the only option to have a biological child with a woman’s own eggs was to rapidly perform an IVF cycle and then cryopreserve the resulting embryos for future transfer. That strategy has substantial disadvantages. It is not applicable to women who are not currently married or with a long-term partner, and it is inappropriate for women with an estrogen-sensitive cancer. Additionally, an IVF cycle usually takes 2 to 3 weeks to initiate and complete (8), causing unacceptable delays for many types of cancer treatment. Furthermore, cost is high at a time when financial stress on the family is maximal. Clinical experience also suggests that women with cancer frequently have unusually poor IVF cycles. Perhaps most important, even if the IVF cycle is of typical quality, the number of embryos obtained is limited (seven to eight on average), and the probability that these embryos, when thawed and transferred to the uterus several years later, will produce a pregnancy is not likely to exceed 40% to 50% (8). The limitations of this method of preserving female reproduction after cancer diagnosis are so substantial that the IVF strategy, though available for over a decade, has only been utilized by a small number of women.
Research on ovarian tissue cryopreservation by Professor Roger Gosden and colleagues in Great Britain now offers the possibility for a much more desirable approach to preserving future reproductive potential. Gosden has shown in experimental animals that ovaries can be removed and thin slices of the ovarian cortex preserved by freezing (9). These cortical slices each contain many thousands of eggs (10). The slices can subsequently be thawed and replaced into the region of the residual ovarian site near the normal fimbriated end of the fallopian tube. Since these are autografts, there is no immunological graft rejection. Sheep so treated have subsequently gone on to have normal ovulatory cycles for at least 2 years, and most important have conceived and borne normal offspring after spontaneous intercourse (9,11). Eggs in slices of human ovarian tissue survive cryopreservation and thawing like animal ovaries (12; Genetics & IVF Institute, unpublished data). It is likely, but not certain, that ovarian tissue from female children can also be cryopreserved like adult ovarian tissue, since all oocytes are fully formed in human beings before birth and remain arrested in meiosis until recruited for ovulation in a given menstrual cycle. The oocytes from children might, in fact, have a higher survival since a greater proportion are primordial follicles, which survive cryopreservation better than more advanced follicles.
Because of this highly important set of observations in experimental animals and the corresponding substantial likelihood that ovarian tissue cryopreservation and autotransplantation will be successful in human beings, Institutional Review Board-approved clinical trials by Gosden's team and our own group are now in progress in women with newly diagnosed cancer. With written informed consent, the specific protocol involves removal of one or both ovaries by minilaparotomy or laparoscopy, and cryopreservation of as many separated cortical slices as can be obtained. Several patients in Great Britain and in the United States have now had ovarian cryopreservation performed, but replacement of ovarian tissue has not yet been undertaken. Replacement of grafts is expected within the next 1 to 2 years, as soon as the primary cancers have been successfully treated and the physicians tell their patients that they can attempt pregnancy.
Given the limited alternatives for women of reproductive age with cancer who may lose their future fertility potential, and the extraordinary results summarized above, ovarian cryopreservation will likely prove clinically useful; this will be a revolutionary improvement in the care of women with cancer. While we recognize as scientists that there can be unanticipated barriers to success with any new reproductive technology, the potential benefit outweighs the limited risks. From initial experience, ovarian cryopreservation appears to be an option of great interest to many women with newly diagnosed cancer, and these women often consider their risk of participation in this protocol to be minimal with the possibility of retaining both normal fertility and hormonal function.
In summary, sperm cryopreservation for future ICSI and ovarian tissue cryopreservation for future autotransplantation are new opportunities to preserve reproductive options of great importance to patients with newly diagnosed cancer. Since patients must utilize these strategies before cancer therapy is initiated, and these patients will not have a future chance to benefit once therapy has damaged gonadal function, awareness of these technologies among oncologists, radiation therapists, and other colleagues who interface with the victims of cancer is a high priority.
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3. Sherins RJ, Thorsell LP, Dorfmann A. et al. Intracytoplasmic sperm injection facilitates fertilization even in the most severe forms of male infertility: pregnancy outcome correlates with maternal age and number of eggs available. Fertil Steril 1995;64:369-375.
4. Bonduelle M, Legein J, Buysse A et al. Prospective follow-up of 423 children born after intracytoplasmic sperm injection. Hum Reprod 1996;11:1558-1564.
5. Sauer MV, Paulson RJ, Ary BA et al. Three hundred cycles of oocyte donation at the University of Southern California: assessing the effect of age and infertility diagnosis on pregnancy and implantation rates. J Assist Reprod Genet 1994;11:92-96.
6. Nagy Z, Cecile J et al. Using ejaculated, fresh, and frozen-thawed epididymal and testicular spermatozoa gives rise to comparable results after intracytoplasmic sperm injection. Fertil Steril 1995;63:808-815.
7. Sherins RJ, Belker AM, Coulam CB et al. Percutaneous nonsurgical sperm aspiration (NSA) from the testis: a highly effective diagnostic and treatment method to achieve pregnancy in azoospermic men. Presented at the Fifty-Second Annual Meeting of the American Society of Reproductive Medicine; November 4, 1996: Boston, MA.
8. Tan SL, Royston P, Campbell S et al. Cumulative conception and livebirth rates after in-vitro fertilization. Lancet 1992;339:1390-1394.
9. Gosden RG, Baird DT, Wade JC et al. Restoration of fertility to oophorectomized sheep by ovarian autografts stored at -196 degrees C. Hum Reprod. 1994;9:597-603.
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11:1484-1486. 11. Baird DT, Webb R, Campbell B et al. Autotransplantation of frozen ovarian strips in sheep results in normal oestrous cycles for at least 22 months. Presented at the Twelfth Annual Meeting of ESHRE;July 2, 1996:Maastricht, Denmark.
12. Newton H, Aubard Y, Rutherford A. et al. Low temperature storage and grafting of human ovarian tissue. Hum Reprod 1996;11:1487-1491.
Copyright (c) 1997 Scientific American, Inc.
From the Genetics & IVF Institute, Fairfax Cryobank, Fairfax, VA and the Medical College of Virginia, Richmond, Virginia.