The Center for Reproductive Medicine and Infertility, Joan and Sanford I. Weill Medical College of Cornell University, 505 East 70th Street, HT-340, New York, NY 10021, USA 1 To whom correspondence should be addressed. e-mail: kuo9001{at}med.cornell.edu
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Abstract |
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Key words: breast cancer/fertility preservation/IVF/ovarian stimulation/tamoxifen
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Introduction |
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As the awareness of the adverse effects of breast cancer chemotherapy on reproduction increases, many patients are seeking assisted reproductive strategies to preserve their fertility. Ovarian cryopreservation and transplantation are experimental strategies that have been used to restore ovarian endocrine function in cancer patients, but no pregnancies have yet been reported in humans (Oktay and Karlikaya, 2000; Oktay et al., 2001
; Oktay and Buyuk, 2002
). Embryo cryopreservation, on the other hand, is an established clinical approach to store excess embryos generated during IVF treatment. This technique has also been used for fertility preservation in cancer patients (Meniru and Craft, 1997
). Unfortunately, because breast cancer cell proliferation and dissemination can be induced by estrogen (Allred et al., 2001
; Prest et al., 2002
), conventional ovarian stimulation regimens are considered by many oncologists to be contraindicated in these patients. Oocyte retrieval and embryo freezing can be performed during unstimulated (natural) cycles in these patients, but typically no more than a single embryo can be obtained (Omland et al., 2001
). Because pregnancy rates increase in parallel with the number of embryos transferred, increasing the number of embryos in storage will boost the patients chance of future pregnancy after cryopreservation (Davis and Rosenwaks, 2001
). In addition, if multiple embryos are stored, patients can thereafter attempt to achieve pregnancy on multiple occasions.
Tamoxifen is a non-steroidal triphenylethylene anti-estrogen that was originally synthesized in the UK as a contraceptive (Harper and Walpole, 1966). It was then found to stimulate follicle growth and used as an ovulation induction agent in Europe (Klopper and Hall, 1971
), while a related compound, clomiphene, became a commonly used ovulation induction agent in the USA (Charles et al., 1966
). It was then discovered that tamoxifen had suppressive effects on breast carcinoma (Jordan, 1976
), and it became a drug of choice in breast cancer treatment and prophylaxis worldwide (Early Breast Cancer Trialists Collaborative Group, 1992
; Mourits et al., 2001
).
In this study, we prospectively studied tamoxifen as an ovarian stimulating agent for IVF, embryo cryopreservation and embryo transfer in breast cancer patients. These were compared with a retrospective group of patients, who had undergone natural cycle IVF (NCIVF). Tamoxifen has been used for the treatment of anovulatory patients for many years (Suginami et al., 1993; Crosignani et al., 1999
) but it has never been used as an ovarian stimulant in IVF cycles. Our aim was to develop a safe ovarian stimulation protocol specific to breast cancer patients. We hypothesized that tamoxifen stimulation would result in higher numbers of embryos compared with NCIVF, while theoretically shielding breast cancer cells against estrogen.
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Materials and methods |
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The control group was retrospectively selected from breast cancer patients who had previously undergone natural cycle IVF to freeze embryos for fertility preservation between 19922000. In NCIVF, no GnRH antagonist or ovarian stimulation was used, and the monitoring, ICSI and embryo cryopreservation/transfer protocols were identical to the tamoxifen group.
Statistics
To compare the percentage of cancelled cycles and the embryos generated per patient between the two groups, Fishers exact test was used. The MannWhitney test was used to compare the number of cycles per patient in each group. ANOVA was used for all other comparisons. Values of P < 0.05 were considered statistically significant.
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Results |
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In the control group (NCIVF), one patient attempted one cycle and four patients attempted two cycles each. The mean number of cycles per patient was similar between the TamIVF and NCIVF groups (1.25 versus 1.8 respectively; P = 0.08). In NCIVF, two patients had four cycles for embryo cryopreservation prior to chemotherapy, and three patients intended to have fresh embryo transfer after being cured from cancer in five cycles. Among these, patient 15 (Table I) attempted IVF because of male factor infertility, which resulted in a term pregnancy. This patient had received chemotherapy 8 years before undergoing IVF. Patient 12 also attempted pregnancy with fresh embryos 18 months after cancer diagnosis, conceived, and delivered a healthy girl. She had only received radiotherapy. In total, of the fresh transfer cycles, 2/6 in TamIVF, and 2/5 in NCIVF resulted in a pregnancy. In NCIVF, one patient attempted pregnancy after thawing two previously frozen embryos, but did not conceive.
In the tamoxifen group, only 1/15 cycles were cancelled due to spontaneous ovulation, a day prior to oocyte retrieval. This patient attempted a second cycle, which resulted in cryopreservation of an embryo. In all other cycles in the tamoxifen group, at least one embryo was generated. Thus, all 12 patients in the tamoxifen group had one or more embryos for cryopreservation or fresh transfer. There was no difference in cycle cancellation rates between those who used GnRH antagonists and those who did not (P = 0.5). In the control group, 4/9 cycles were cancelled (P < 0.05), and an embryo was generated in only 3/5 patients (P = 0.07). In two cycles, patients ovulated prior to retrieval; in one, follicle growth halted at an early stage and in the other no fertilization occurred. A 44 year old patient (patient 11) underwent three consecutive IVF cycles. Interestingly, the first two unstimulated cycles did not yield an embryo, while the third cycle with tamoxifen resulted in an embryo. Patient 12 underwent NCIVF at ages 38 and 39, followed by a TamIVF at the age of 42, which all resulted in the generation of a single embryo.
Mean follow-up after the completion of the IVF procedures was 15 ± 3.6 months (range 354). All patients were recurrence free, and had survived at the time of this report.
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Discussion |
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There were five cycles where GnRH antagonists were used to prevent a spontaneous LH surge in TamIVF. In these cases, follicle growth was maintained with hMG administration. One can question whether this was responsible for the improved outcome. However, there was no difference in peak estradiol, number of mature oocytes recovered, and embryos generated between the patients who used GnRH + hMG and those who did not. This is not surprising because we used GnRH antagonists only during the last 12 days of stimulation, after follicles were recruited. Interestingly, we had excluded a rectal cancer patient who had NCIVF for embryo cryopreservation prior to chemo- and radiotherapy, and who used GnRH antagonists and hMG. This patients peak estradiol was 198 pg/ml; only one mature oocyte was obtained but the cycle was cancelled due to failed fertilization. It is still possible, however, that the difference in cycle cancellation rates between NCIVF and TamIVF was at least partly due to antagonist use. Thus we see antagonist use as an integral part of our protocol. Because of lack of a flare-effect (Reissmann et al., 1995), antagonists are more suitable for breast cancer patients than the GnRH agonists.
Another estrogen agonist/antagonist drug related to tamoxifen is clomiphene. However, we chose tamoxifen because of the extensive clinical experience in the treatment of breast cancer with this agent, and laboratory evidence that it has a better suppressive effect on cell proliferation and tumorigenesis (Marth et al., 1984). Another advantage of tamoxifen is that, in contrast to clomiphene, it does not antagonize endometrial development (Marttunen et al., 2001
). Clomiphenes antagonistic effect can result in suboptimal endometrial development for embryo implantation in some patients (Cook et al., 1984
; Fritz et al., 1987
; Massai et al., 1993
). Even though no published study has compared tamoxifen to clomiphene vis-a-vis IVF success rates, tamoxifen at least does not appear to alter implantation rates, as has been suggested for clomiphene (Gerhard and Runnebaum, 1979
; Messinis and Nillius, 1982
; Boostanfar et al., 2001
). In those patients undergoing fresh embryo transfer, this may prove to be another advantage of TamIVF.
We also report the occurrence of pregnancy and live birth after tamoxifen stimulation, IVF and embryo transfer. This is, to our knowledge, the first report of IVF pregnancy after tamoxifen stimulation. However, because most patients in the tamoxifen group cryopreserved their embryos and have not yet undergone embryo transfer, and, in contrast, most patients in the NCIVF group had a fresh embryo transfer, we are not yet able to compare pregnancy rates between these two protocols.
Of the two patients who conceived in the tamoxifen group, one miscarried at 8 weeks of pregnancy. This patient was 42 years old, and her risk of spontaneous abortion was already high due to her age. The other patient recently delivered a healthy set of twins. Thus, we could not provide long-term data on the effects of tamoxifen on pregnancy outcome. However, tamoxifen has been used extensively for ovulation induction in anovulatory patients in other countries (Gerhard and Runnebaum, 1979; Ruiz-Velasco et al., 1979
; Messinis and Nillius, 1982
), and recently in the USA (Boostanfar et al., 2001
) without any adverse effects on fetal development. Moreover, one study reported lower miscarriage rates with tamoxifen, compared with clomiphene (Wu, 1997
). These studies also show comparable pregnancy rates between tamoxifen and clomiphene stimulated patients and indicated that tamoxifen was better tolerated. Concerns have been raised regarding the safety of tamoxifen administration in women attempting pregnancy, based mainly on studies in laboratory animals (Furr et al., 1976
; Sweet and Kinzie, 1976
; Sadek and Bell, 1996
; Halakivi-Clarke et al., 2000
) and a few case reports of dissimilar anomalies (Cullins et al., 1994
; Tewari et al., 1997
) which did not establish a causeeffect relationship. In contrast, the long-term experience with tamoxifen, and its close relative clomiphene, in ovulation induction does not suggest a teratogenic effect. Moreover, when used for the purpose of ovarian stimulation, the drug is discontinued prior to ovulation or oocyte retrieval. In the case of IVF, early stage embryos are not exposed to tamoxifen as fertilization takes place in vitro. Further support giving evidence for the safety of tamoxifen use in assisted reproduction is found in a previous study that showed a lack of detrimental effects of tamoxifen on oocyte and early embryo development (Fisk et al., 1989
). In that study, volunteers undergoing tubal ligation procedures were given 80 mg of tamoxifen on the day before oocyte retrieval. Even though tamoxifen was detected in substantial amounts in follicular fluids of patients, there was no statistical difference in fertilization rates in vitro between tamoxifen-treated patients and controls (80 and 68% respectively). In addition, the morphological characteristics of the oocytes, the rates of cleavage and the concentrations of estradiol, progesterone and androstenedione in follicular fluid were similar in the two groups. These results suggest that even high-dose tamoxifen does not adversely affect the final stages of maturation or the fertilization and early cleavage of human oocytes. Consistent with the latter study, there has been one published case report of a male fetus exposed to tamoxifen throughout the entire pregnancy. Even though the birth was premature, no congenital anomalies were noted (Isaacs et al., 2001
). Based on this evidence, it appears that the short-term administration of tamoxifen for ovarian stimulation does not pose a risk to the fetus, and in fact it has been used extensively for ovulation induction in Europe and elsewhere. However, because of the long half-life of tamoxifen, women who are on long-term tamoxifen therapy may have higher serum levels of tamoxifen, and should not conceive while taking this drug.
Peak estradiol levels were higher in the TamIVF than the NCIVF and this may raise concerns regarding stimulation of breast cancer cells. When patients are placed on long-term tamoxifen therapy for breast cancer treatment and prophylaxis, mean estradiol levels are chronically elevated, and can be much higher than the peak levels reported in our study (Shushan et al., 1996; Klijn et al., 2000
). Yet, tamoxifen reduces breast cancer incidence in these patients, indicating that this drug can even block the effects of supraphysiological levels of estrogen on breast tissue. Nevertheless, aromatase inhibitor drugs have recently been used in ovulation induction (Fisher et al., 2002
), and we are conducting a prospective study to test their value for fertility preservation in breast cancer patients as they may not result in a rise in estradiol levels.
Short-term use of tamoxifen for ovarian stimulation and embryo transfer or cryopreservation appears to be a feasible method of fertility preservation in breast cancer patients. However, this study had several limitations; the NCIVF group was retrospective and small, and the follow-up of cases with TamIVF was relatively short. Longer follow-up will be required to determine the pregnancy rates with cryopreserved embryos after TamIVF. To maximize the patients future chance of pregnancy, women of reproductive age with breast cancer should be referred to an appropriate assisted reproduction centre as soon as the diagnosis is made in order to enable patients to discuss their options for fertility preservation.
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Acknowledgments |
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References |
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Submitted on July 31, 2002; accepted on October 12, 2002