Women with cancer undergoing ART for fertility preservation: a cohort study of their response to exogenous gonadotropins Cancer patients produce similar numbers of oocytes after ovarian hyperstimulation compared with age-matched infertile controls, suggesting that malignancy does not adversely affect ovarian response. (Fertil Steril 2009; 91:1476–8. 2009 by American Society for Reproductive Medicine.)
It is estimated that approximately 113 per 100,000 women under the age of 50 are diagnosed with a malignancy each year in the United States (1). However, as a result of early detection programs and advancements in treatment protocols, women with cancer are now able to live substantially longer and lead more productive lives. Therefore, quality of life issues, such as maintaining fertility potential, have become important areas of research (2). It is well known that surgery, chemotherapy, and/or radiotherapy administered during the adolescent or reproductive years can leave cancer survivors unable to fulfill their desire for fertility. Developments in the fertility preservation arena, in conjunction with increased cancer survival rates, have heightened the awareness of both patients and health care providers regarding fertility preservation (3). Such advancements have led the American Society of Clinical Oncology (ASCO) to release recommendations stating that clinicians should counsel reproductive-age women with cancer regarding methods available for fertility preservation (4). Currently, only sperm and embryo cryopreservation are considered to be standard ‘‘nonexperimental’’ procedures by the American Society of Reproductive Medicine and the ASCO (5). Other potential fertility preservation methods include: oocyte cryopreservation (of both mature and immature oocytes), ovarian tissue cryopreservation, ovarian tissue transplantation, and ovarian suppression (6). Of these procedures, mature oocyte cryopreservation is most commonly performed, and at least for the time being, is the most promising. Though it is still labeled ‘‘experimental,’’ some clinics are reporting acceptable pregnancy rates after egg freezing (7–12). With continued reports of success, these techniques should soon elevate from the experimental arena to standard-of-care practice, providing additional readily available fertility-preserving options for women whose cancer treatment cannot be delayed, who do not have a male partner, or are still of adolescent age. Received May 18, 2008; revised June 24, 2008; accepted July 9, 2008; published online September 18, 2008. J.K. has nothing to disclose. N.N. has nothing to disclose. S.T. has nothing to disclose. L.K. has nothing to disclose. J.G. has nothing to disclose. F.L. has nothing to disclose. Reprint requests: Jaime M. Knopman, 660 First Avenue, Fifth Floor, New York, NY 10016 (FAX: 212-263-0059; E-mail: [email protected]
Review of the male literature has shown that malignancy, specifically testicular cancer and lymphoma, adversely affects fertility, even before the initiation of cancer treatment (13–16). It is hypothesized that these malignancies directly impair spermatogenesis and Leydig cell function, causing a decrease in sperm concentration and motility, as well as alter immunologic responses, thereby impairing fertility potential. Whether the presence of cancer (gynecologic or other) in a female patient affects ovarian response to gonadotropin hyperstimulation has been examined in only one small case series (17). That review demonstrated deterioration in the quality and behavior of oocytes retrieved from cancer patients before treatment, suggesting that malignancy in the female patient, similar to their male counterparts, adversely affects fertility. However, the numbers in that case series were small. Therefore, the objective of the present study was to further investigate this notion and determine whether women with a cancer diagnosis, before receiving radiation or chemotherapy, show a reduced response to ovarian hyperstimulation when preserving oocytes or embryos for future use. From January 2001 to December 2006, 28 patients diagnosed with cancer sought fertility preservation at the New York University Fertility Center. Before initiation of any fertility treatment, day 2 E2 and FSH levels were assessed. All but one patient were hyperstimulated with injectable gonadotropin therapy in conjunction with GnRH antagonist suppression; one woman received GnRH agonist downregulation in the luteal phase before ovarian hyperstimulation, followed by gonadotropin treatment. All patients in the control group of male-factor patients were hyperstimulated with injectable gonadotropin therapy in conjunction with GnRH antagonist suppression. No patients received aromatase inhibitors or antiestrogen therapy. An hCG (simulated LH) trigger was administered when at least two follicles reached 17 mm in diameter; ultrasound-guided transvaginal oocyte retrieval was then performed in routine fashion approximately 36 h later. Serum E2 levels were periodically assessed throughout the stimulation period and always on the day of hCG administration. Oocytes were harvested in routine fashion, and all mature eggs were either
Fertility and Sterility Vol. 91, No. 4, Supplement, April 2009 Copyright ª2009 American Society for Reproductive Medicine, Published by Elsevier Inc.
cryopreserved as unfertilized gametes or fertilized using conventional insemination methods or intracytoplasmic sperm injection approximately 4 h after oocyte retrieval. Oocytes were cryopreserved using either vitrification or slow-freezing methods approximately 3 h after retrieval. The number of oocytes retrieved in the cancer study population was compared with 135 age-matched controls (selected to give a control-to-study patient ratio of 4:1) undergoing IVF for male-factor infertility from January 2001 to December 2006. Patients with other infertility diagnoses were excluded from the control population. All oocytes exposed to male gamete prefreeze underwent assessment for fertilization approximately 18 h after retrieval; the normal fertilization process was documented by the presence of two pronuclei (2PN). Primary cycle outcome measures included serum E2 level on day of hCG trigger and the number of oocytes collected at time of retrieval. Additional outcome measures include baseline day 2 or 3 serum FSH and E2 levels, as well as total gonadotropin dosage required to achieve hyperstimulation. All data were analyzed using the Mann-Whitney test. Institutional Review Board approval was obtained for the study. The mean age of the cancer patients was 34 5.1 (range 20–41) years and 35.4 3.5 (range 20–41) years for the age-matched infertile controls (P¼.26). Individual cancer diagnoses for the study population were as follows; 10 breast, 4 uterine, 4 Hodgkin, 4 ovarian, 1 thymoma, 1 multiple myeloma, 1 acute myeloblastic leukemia, 1 cervical, 1 colon, and 1 Ewing sarcoma. Nineteen of 28 patients diagnosed with a malignancy elected embryo cryopreservation, four chose to have both oocytes and embryos frozen, and five elected oocyte cryopreservation only. Of note, oocyte cryopreservation was not offered to patients before 2005. The mean baseline serum FSH and E2 levels were 7.5 3.2 mIU/mL and 35 15 pg/mL, respectively, for the study population and 8.3 2.6 mIU/mL and 35 13.5 pg/mL, respectively, for the control subjects (P¼NS). The total gonadotropin dosage required to achieve adequate stimulation in the study population was 3,507 1,012 IU, which
was not different from that used in the control subjects (3,306 1,164 IU; P¼.38). When evaluating the study versus control groups (age range 20–41 years), the average serum E2 level on the day of hCG trigger in the cancer group was 1,515 712 pg/mL, compared with 1,393 769 pg/mL in the control patients (P¼.23). The main study groups were then subdivided by age into younger (age range 20–33 years) and older (age range 34–41 years) groups and compared with corresponding age-matched IVF controls. The mean E2 level on day of hCG administration in the younger cancer patients was 1,771 740 pg/mL, which was not significantly different than the younger control subjects (1,672 1,052 pg/mL; P¼.34). Similarly, the mean E2 levels in older cancer patients (1,350 662 pg/mL) was not significantly lower than age-matched control subjects (1,392 60 pg/mL; P¼.70). Thus, when both younger and older cancer patients were compared with parallel age-matched cohorts in the general IVF population, serum E2 levels on the day of hCG were not found to be significantly significant (Table 1). The average number of oocytes retrieved in all cancer patients (ages 20–41 yrs) was 14 9 oocytes compared with 12 7 oocytes for control subjects (P¼.48). Comparative groups were then subdivided by age as in the preceding paragraph. The average number of oocytes retrieved in younger cancer patients was 18 9 oocytes compared with 15 8 oocytes in age-matched IVF controls (P¼.18). Similarly, the average number of oocytes retrieved in older cancer patients was 11 9 compared with 11 6 in the age-matched counterpart group (P¼.76). Thus, the total number of oocytes retrieved in cancer patients was not statistically different than that of the general IVF population. When the number of oocytes retrieved from younger cancer patients (18 9) was compared with that of the older study group (11 9), the younger patients had significantly more eggs (P¼.04). We cannot comment on embryo quality in our study population, because gametes were frozen as unfertilized oocytes or 2PN zygotes, and as of writing only one
TABLE 1 Average serum E2 level on day of hCG trigger and number of oocytes retrieved in cancer patients versus age-matched controls. Age 20-41 yrs Cancer patients
Age 20-33 yrs Cancer patients
Age 34-41 yrs Cancer patients
Mean E2 level on day 1515 712 1852 1021* 1771 740 2037 1057* 1350 662 1667 925* of hCG (pg/mL) Mean no. of oocytes 14 9 14 7* 18 9 16 8 11 8 12 7* * P¼NS. Knopman. Cancer and ovarian hyperstimulation. Fertil Steril 2009.
Fertility and Sterility
patient had returned to use her cryopreserved embryos (this cycle resulted in the delivery of a viable female infant). Reproductive-age women treated for malignancies are often rendered amenorrheic and infertile as a result of cancer treatment. Although the likelihood of menses returning is higher in women receiving treatment at a younger age (<25 yrs), this does not always correlate with normal ovarian function and fertility (6). The risk of permanent amenorrhea has driven both patients and physicians to explore fertility preservation options in women diagnosed with cancer during reproductive age. Embryo cryopreservation and, more recently, oocyte cryopreservation (after ovarian hyperstimulation) are two options (6, 18–22). However, for either of these methods to be successful, an appropriate quantity of oocytes must be obtained. The male literature suggests that malignancy adversely affects fertility by reducing the quality and quantity of sperm (23). Whether cancer, before treatment, in female patients has the same affect on oocytes and their ability to be stimulated via superovulation protocols has been evaluated in only one small case series (17). In the present study, we demonstrate that female cancer patients produce oocyte numbers similar to the general IVF population after ovarian hyperstimulation, suggesting that ovarian reserve, as measured by day 3 hormonal assessments and oocyte quantity, is not affected by malignancy. Similar to a control population, age appears to be the primary determinant in the quantity of oocytes obtained in cancer patients who have yet to undergo cancer-treating therapy. Other authors have reported obtaining significantly fewer oocytes from cancer patients than we report here. Our higher oocyte yield is most likely due to differences in ovarian stimulation methods (24). As patients return to use their cryopreserved embryos and oocytes, we will provide long-term follow-up and comment on embryo quality, pregnancy outcome, and overall patient health status relative to fertility preservation after a cancer diagnosis. In addition, we hope to add more patients to establish whether there is a relationship between a specific cancer type and response to gonadotropins. So far, our experience demonstrates that women with cancer respond adequately to conventional ovarian hyperstimulation, further supporting the role of gamete/embryo cryopreservation as a means of preserving fertility in age-appropriate female cancer patients. Jaime M. Knopman, M.D. Nicole Noyes, M.D. Sheeva Talebian, M.D. Lewis C. Krey, Ph.D. James A. Grifo, M.D., Ph.D. Frederick Licciardi, M.D. Department of Obstetrics and Gynecology, New York University Medical Center, New York, New York
Knopman et al.
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