Ovarian response to controlled ovarian hyperstimulation in cancer patients is diminished even before oncological treatment

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1 Ovarian response to controlled ovarian hyperstimulation in cancer patients is diminished even before oncological treatment Javier Domingo, M.D., a Vicente Guillen, M.D., a Yanira Ayllon, M.D., a María Martínez, M.D., b Elkin Mu~noz, M.D., c Antonio Pellicer, M.D., d and Juan A. Garcia-Velasco, M.D. b a IVI Las Palmas, Las Palmas, b IVI Madrid, Rey Juan Carlos University, Madrid; c IVI Vigo, Vigo, and d IVI Valencia, Valencia University, Valencia, Spain Objective: To evaluate the results of controlled ovarian stimulation before chemotherapy for oocyte vitrification to preserve fertility in women diagnosed with cancer and compare them with a historical control group. Design: A retrospective, multicenter, observational study performed between March 2007 and January Setting: University-affiliated infertility clinics. Patient(s): Of 272 patients affected by cancer in our Fertility Preservation Program, 223 women underwent a stimulated cycle for oocyte vitrification according to our protocols before cancer treatment. Their results were compared with a historical control group of 98 patients diagnosed with male factor infertility who were stimulated for a conventional IVF cycle. Intervention(s): Controlled ovarian stimulation and oocyte retrieval. Main Outcome Measure(s): Days of stimulation, total dose of gonadotropins, estrogen levels, and number of oocytes retrieved and vitrified. Result(s): No differences were found in days of stimulation, but significant differences in E 2 levels and the number of retrieved oocytes were measured, especially in the hormone-dependent cancer group. Conclusion(s): Patients with hormone-dependent cancer had a weaker response to controlled ovarian stimulation compared with patients with non-hormone-dependent cancer. Whether the oncological disease already affects the ovaries before chemo-/radiotherapy remains to be elucidated. (Fertil Steril Ò 2012;97: Ó2012 by American Society for Reproductive Medicine.) Key Words: Fertility preservation, cancer, ovarian stimulation, oocyte vitrification The increase in survival rates for cancers affecting children and adults of reproductive age has led to an increased interest in fertility preservation. In women under 40 years of age, cancer incidence is 7%, but survival rates are roughly 70% (1 5). Recent data from the American Cancer Institute indicate that nearly 250,000 cancer survivors are women of reproductive age, between 20 and 39 years old, with breast cancer being the most frequent in this age group (2, 3). Owing to the gonadotoxicity of Received November 7, 2011; revised December 27, 2011; accepted January 5, 2012; published online January 26, J.D. has nothing to disclose. V.G. has nothing to disclose. Y.A. has nothing to disclose. M.M. has nothing to disclose. E.M. has nothing to disclose. A.P. has nothing to disclose. J.A.G.-V. reports grants and payments for lectures from MSD, Merck Serono, and Ferring. Supported by FIS PI11/02747 from Ministerio de Ciencia e Innovacion, Madrid, Spain. Reprint requests: Juan A. Garcia-Velasco, M.D., IVI Madrid, Av del Talgo 68, Madrid, Spain ( juan.garcia.velasco@ivi.es). Fertility and Sterility Vol. 97, No. 4, April /$36.00 Copyright 2012 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert chemotherapy and radiotherapy, 42% of young women will develop premature ovarian failure (6, 7). Among the different fertility preservation approaches available, ovarian tissue freezing and oocyte vitrification are the main options. Ovarian tissue cryopreservation is a viable option for fertility preservation, especially in women who cannot delay the start of chemotherapy and/or for prepubertal girls; so far, 17 live births have been obtained to date with this technique. Oocyte vitrification offers young patients, in the event that they become infertile, the possibility of freezing eggs for their future reproductive life for a short period of time, avoiding general surgery for ovarian tissue extraction or bypassing the necessity to create embryos that may cause moral dilemmas for some patients. Interestingly, recent reports have shown that some young women diagnosed with cancer exhibit a weaker response to controlled ovarian stimulation (COH) than expected for their age, raising the possibility that the disease affects the gonads before chemo- or radiotherapy (8). The aim of our study was to evaluate the ovarian response to stimulation in patients with recently diagnosed cancer before starting chemotherapy. MATERIALS AND METHODS A total of 272 patients were enrolled since we started the Fertility 930 VOL. 97 NO. 4 / APRIL 2012

2 Fertility and Sterility Preservation Program for patients with cancer at our institution in March According to the type and timing of chemotherapy, type of cancer, and patient s age, patients were asked to decide between oocyte vitrification and ovarian tissue freezing. A total of 223 patients (mean age, 32.0 years) underwent COH for oocyte vitrification. Ovarian tissue freezing was chosen by eight women, and 41 opted not to undergo any treatment owing to different reasons: lack of time to complete COH and unwillingness to undergo laparoscopy with general anesthesia (20), nonconformity with the concept and uncertainties of the expectations (13), lack of oncologist s agreement (6), or ineligibility for medical reasons (2). Four patients opted for the combined approach: vitrified oocytes and later cryopreserved ovarian cortex. All women in the study were >18 and <40 years of age and recently diagnosed with cancer, had ovarian function, and planned to receive chemotherapy and/or radiotherapy. The medical oncologist s agreement and authorization was obtained for all patients. The historical control group included 98 healthy, age-matched women (mean age 31.9 years) who were treated with COH-IVF owing to severe male factor infertility during the same time period. The control and experimental groups had comparable baseline characteristics. Fifteen cycles of cancer patients were cancelled for different indications: seven cycles were self-cancelled, five cycles were cancelled for low or nonresponse, one cycle because the patient required emergency surgery due to medical reasons, and two cycles because of premature ovulation. No other fertility preservation modality was offered to these patients. One patient in the control group cancelled the cycle herself. Stimulation Protocol Our COH protocol did not change throughout the duration of the program (Fig. 1). In non-hormone-dependent (HD) cancers and control patients, COH was performed using a similar protocol: starting recombinent FSH (rfsh) on day 2 or 3 of a spontaneous cycle under a GnRH antagonist protocol with letrozole not being administered. In HD cancer patients, aromatase inhibitors were used for ovarian stimulation. Letrozole 5 mg/day (Femara 2.5 mg; Novartis) was administered orally starting the second or third day of a spontaneous cycle until the day of triggering and then until the first day of menstruation after oocyte retrieval. After 2 days of letrozole administration, IU/day of rfsh (Gonal F; Merck-Serono) was added. GnRH antagonist 0.25 mg/day (Cetrotide; Merck- Serono) was administered when the leading follicle reached 14 mm, and final oocyte maturation was triggered with 0.2 mg of GnRH agonist triptorelin (Decapeptyl 0.1, Ipsen- Pharma) as soon as two follicles were R20 mm. Statistical Analysis To compare two pairs of averages, t-tests were used with Levene tests to confirm or dismiss equal variance. When more than two pairs of averages existed, Kruskal-Wallis tests were used to calculate differences, and the Jonckheere- Terpstra test for trend was used when Kolmogorov- Smirnov-Wilk criteria for normality of distribution were not met. The analyses obtained a 95% confidence interval (CI) from the mean and a significance level of <.05. The analyses were performed using the Statistical Program for Social Sciences, version RESULTS Breast cancer was the most frequently diagnosed cancer among patients who desired fertility preservation (68.7%), followed by Hodgkin s lymphoma (13%) and non-hodgkin s lymphoma (5%). Patient demographics are provided in Table 1. The mean time required to start ovarian stimulation in our study was 9.5 days (range, 0 77 days) from the first consultation, with a mean length of stimulation of 9.1 days (range, 4 18 days). The mean length of stimulation in the non-hd cancer patients with only rfsh was 8.7 days, whereas the HD cancer patients stimulated with letrozole plus rfsh had significantly longer treatment, 9.6 days (P¼.002; 95% CI, ). The total dose of gonadotropins used was comparable among groups (1,803 IU [1,587 2,018] vs. 1,755 IU [1,592 1,917] vs. 1,947 IU [1,760 2,133]; P¼.29) for the non-hd cancer group, HD group, and control group (Table 1). FIGURE 1 Schematic representation of the protocols used in the three groups of patients. VOL. 97 NO. 4 / APRIL

3 TABLE 1 Patient demographics according to the type of stimulation. Non-HD, antagonist FSH (n [ 66) HD, letrozole FSH (n [ 142) Control (n [ 97) Age Days of stimulation a Total FSH, IU 1, ,755 1,114 1, Peak serum E 2, pg/ml 1,744 1, a 2,109 1,260 Retrieved oocytes a % MII oocytes a P<.05. As expected, serum E 2 levels were significantly lower when letrozole was used in patients with HD cancer (381 vs. 1,744 pg/ml in the non-hd group; P<.001, 95% CI 1,102 1,623), as we aimed to keep E 2 levels as low as possible (Table 1). The mean number of oocytes retrieved in the cancer patients group was 10.5 oocytes (range, ), and it was 12.4 (range, ) in the control group (P¼.02; 95% CI, ). When we compared the number of oocytes retrieved according to the type of protocol used, the HD group had the lowest number, with 2.4 (range, ) fewer oocytes than in the non-hd group (9.8 vs oocytes; P¼.003; Table 2). The mean number of metaphase II (MII) oocytes in the cancer patients group was , whereas the mean in the control group was (P¼.03; 95% CI, ). We did not find significant differences in the percentage of MII oocytes obtained according to the COH protocols used: 75.3% in the antagonist plus rfsh group and 74.4% in the letrozole-rfsh group. A weak response (four or fewer oocytes) was more frequently observed in the cancer patients group than in the control group (21.2% vs. 2.6%; P<.001). A moderate response (five to eight oocytes) was obtained in 19.2% of cases. Thus, 40% of the patients in the cancer patients group had eight or fewer oocytes, whereas only 27.3% of the control group had eight or fewer oocytes (P¼.04). According to the COH protocol used, 23.5% of the HD cancer patients treated with letrozole had four or fewer oocytes and 9.3% of the non-hd group had four or fewer oocytes (P¼.001; odds ratio, 2.99; 95% CI, ). The cancellation rate owing to a weak response in the cancer patients group was 2.5%, and it was 1.3% in the control group (P¼.1). TABLE 2 Mean differences for serum E 2 level, retrieved oocytes, and vitrified (MII) oocytes according to the different stimulation protocols used. Serum E 2 level Oocytes MII oocytes Cases vs 1,412 a (1, ) 1.9 b ( ) 1.6 b ( ) controls HD vs. Non-HD 1,362 a ( ) 2.4 a ( ) 1.9 a ( ) a P<.005. b P<.05. No correlation was found between age and the ovarian response to COH after stratifying data (Fig. 2). The correlation with diagnosis was not evaluated because all HD cancers were stimulated with letrozole and all other types of non-hd cancer with only rfsh. Similarly, no patient in the control group received letrozole treatment. DISCUSSION Although oncological treatments may lead to sterility due to an increased risk of premature ovarian failure in most cancer patients (9), fertility preservation before the initiation of chemo-/radiotherapy may provide these patients an opportunity to conceive a child with their own gametes once they are cured of their disease. Among the different options, oocyte/ embryo cryopreservation is the most accepted approach. However, as we have observed, these young cancer patients may already have a compromised ovarian reserve before the start of oncological treatment. Oocyte vitrification, when offered to cancer patients, combines some great advantages with a few drawbacks. The main advantages are the efficiency and reproducibility of the technique, which can be managed on an outpatient basis (10). However, the main criticism may come from (a) not being the gold standard for fertility preservation in fact, to the best of our knowledge, the only pregnancy described is a combination of egg vitrification and ovarian cortex orthotopic transplantation, not egg vitrification alone (11) and (b) the need for COH to obtain the oocytes, which delays the initiation of chemotherapy and may allow elevated E 2 levels. According to American Society of Clinical Oncology and American Society for Reproductive Medicine guidelines (12), the only proven fertility preservation option is embryo cryopreservation, which has been the only method available with consistent results thus far, but due to the improvements in both oocyte vitrification and ovarian tissue cryopreservation, they are being routinely performed in many countries. Oocyte freezing offers young women, most of whom are single with no partner, the possibility of avoiding the ethical considerations of creating embryos with donated sperm (10, 13). The need for general anesthesia, the surgical risks associated with laparoscopy, and the need to remove a half or full ovary in young women are reasons enough to consider that ovarian tissue cryopreservation is not so attractive to all patients. Furthermore, the limited duration of the frozen/thawed 932 VOL. 97 NO. 4 / APRIL 2012

4 Fertility and Sterility FIGURE 2 Mean number of retrieved oocytes stratified by patient s age. ovarian cortex implant, the possibility of reseeding tumor cells with the reimplant (14 16), and the lack of data for failed attempts make this approach experimental. However, live born have been described either alone (17) or in combination with COH and oocyte vitrification after ovarian transplantation (11, 18). The fact that COH is required to obtain mature oocytes to vitrify creates some controversy among clinicians, especially among oncologists. Oktay et al. (19, 20) described the use of aromatase inhibitors along with COH as a safe approach for obtaining a reasonable number of mature oocytes with serum E 2 levels similar to natural ovulation cycles, although no pregnancies have yet been described in cancer patients using this approach. If GnRH agonists are used to trigger ovulation instead of hcg, the luteal phase will be shorter and steroid concentrations lower (21), which can be reduced even more if we maintain aromatase inhibitors during the luteal phase until menses reappear (22). In our patients with HD cancer, we confirmed that serum E 2 levels did not increase above 381 pg/ml, and menstruation resumed in approximately 5 days. Another option to avoid increasing E 2 levels might be immature oocyte retrieval for further in vitro maturation, but the efficiency of the technique is still not satisfying and less reproducible than mature oocyte vitrification (23). The ovarian response to COH is crucial for successful fertility preservation, but in our patients the oocyte yield was significantly lower than in an age-matched group. Interestingly, previous studies have shown a weaker response in women with cancer (8, 24), which was unexpected because these women had not yet received chemo-/radiotherapy. This observation could be due to a higher catabolic status associated with the illness itself, which would increase stress hormone levels such as prolactin and endogenous opiate production, suppressing gonadotropin levels (8). Another possibility could be the need to start COH as soon as possible, which may force the clinician to start on any given cycle day. However, according to recent evidence (25), this approach does not seem to affect the ovarian response. An attractive hypothesis to explain this low-level response involves carriers of BRCA 1-2 mutations, who seem to have fewer oocytes after ovarian stimulation compared with those who lack the mutation (26). However, not all investigators agree, and discordant results have been obtained in women carrying BRCA 1-2 mutations (27).A final explanation could be a shortening of the telomere length and reduced telomerase activity in granulosa cells, as observed in young women with occult ovarian insufficiency (28). Generally speaking, the cancellation rate in this group of patients was low (2.5%). We should keep in mind that the aim of this approach is to offer the possibility to conceive in the future, and usually there is no time for a second ovarian stimulation. Thus, a tendency exists to carry on with the stimulation even when a weak response is observed. Low and very low levels of response were observed in protocols with letrozole, which was used only in breast cancer patients. We observed that 23.5% of all breast cancer patients had a weak response, versus 9.3% of non-hd tumors (odds ratio, 2.99; 95% CI, ). Thus, the risk of a weak response in breast cancer patients was 3 times higher than in the non-hd patients. Evaluating the status of the BRCA mutation in our patients would have been interesting, but this information was not available. The main limitation of our study is the fact that letrozole was used in all breast cancer patients, whereas it was not used in non-hd tumors, thus the lower response could be due not only to the oncological disease but to the differences in the COH protocol. Although this is an unlikely hypothesis according to previous experiences with aromatase inhibitors in other indications (29), we cannot rule out an impact of letrozole on ovarian response in breast cancer patients. In conclusion, patients with cancer exhibited a weaker response to COH before starting oncological treatment, especially those with HD tumors, although a protocol-dependent bias may be involved. Whether the cancer affects the ovaries is a matter of debate. Additional basic studies are needed to elucidate these findings. VOL. 97 NO. 4 / APRIL

5 Acknowledgments: The authors thank the IVI Foundation and all embryologists and gynecologists working for our Fertility Preservation Program at the IVI clinics. We would also like to express our gratitude to Merck Serono-Spain for providing the medication for our oncology patients. REFERENCES 1. Linet M, Ries L, Smith MA, Tarone RE, Devesa SS. Cancer surveillance series: recent trends in childhood cancer incidence and mortality in the United States. J Natl Cancer Inst 1999;91: Surveillance, Epidemiology and End Results Program, USA: Division of Cancer Control and Population Sciences, National Cancer Institute; Rodríguez-Wallberg KA, Oktay K. Fertility preservation in women with breast cancer. Clin Obstet Gynecol 2010;53: Del Mastro L, Giraudi S, Levaggi A, Pronzato P. Medical approaches to preservation of fertility in female cancer patients. Expert Opin Pharmacother 2011;12: Sonmezer M, Oktay K. Fertility preservation in young women undergoing breast cancer therapy. 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Twins born after transplantation of ovarian cortical tissue and oocyte vitrification. Fertil Steril 2010;93:268.e Lee SJ, Schover LR, Partridge AH, Patrizio P, Wallace WH, Hagerty K, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006;24: Kuwayama M, Vajta G, Kato O, Leibo SP. Highly efficient vitrification method for cryopreservation of human oocytes. Reprod Biomed Online 2005;11: Meirow D, Hardan I, Dor J, Fridman E, Elizur S, Ra anani H, et al. Searching for evidence of disease and malignant cell contamination in ovarian tissue stored from hematologic cancer patients. Hum Reprod 2008;23: Dolmans M, Marinescu C, Saussoy P, Van Langendonckt A, Amorim C, Donnez J. Reimplantation of cryopreserved ovarian tissue from patients with acute lymphoblastic leukemia is potentially unsafe. Blood 2010;116: Sanchez-Serrano M, Novella E, Rosello E, Camarasa N, Teruel J, Pellicer A. Malignant cells are not found in ovarian cortex from breast cancer patients undergoing ovarian cortex cryopreservation. Hum Reprod 2009;24: Donnez J, Dolmans M, Demylle D, Jadoul P, Pirard C, Squifflet J, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 2004;364: Donnez J, Silber S, Andersen CY, Demeestere I, Piver P, Meirow D, et al. Children born after autotransplantation of cryopreserved ovarian tissue: a review of 13 live births. Ann Med 2011;43: Oktay K, Hourvitz A, Sahin G, Oktem O, Safro B, Cil A, et al. Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy. J Clin Endocrinol Metabol 2006;91: ACOG Committee Opinion. Aromatase inhibitors in gynecologic practice. Obstet Gynecol 2008;112: Humaidan P, Kol S, Papanikolaou E. GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Hum Reprod Update 2011; 17: Garcia-Velasco JA, Moreno L, Pacheco A, Guillen A, Duque L, Requena A, et al. Aromatase inhibitor letrozole increases the concentration of intraovarian androgens and improves in vitro fertilization outcome in low responder patients: a pilot study. Fertil Steril 2005;84: Ata B, Shalom-Paz E, Chian RC, Tan SL. In vitro maturation of oocytes as a strategy for fertility preservation. Clin Obstet Gynecol 2010;53: Bath E, Wallace WHB, Shaw MP, Fitzpatrick C, Anderson RA. Depletion of ovarian reserve in young women after treatment for cancer in childhood: detection by anti-mull erian hormone, inhibin B and ovarian ultrasound. Hum Reprod 2003;18: S onmezer M, T urkc uoglu I, Coskun U, Oktay K. Random-start controlled ovarian hyperstimulation for emergency fertility preservation in letrozole cycles. Fertil Steril 2011;95:2125.e Oktay K, Kim JY, Barad D, Babayed SN. Association of BRCA1 mutations with occult primary insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks. J Clin Oncol 2010;28: Pal T, Keefe D, Sun P, Narod S. The hereditary breast cancer clinical study group. Fertility in women with BRCA mutations: a case-control study. Fertil Steril 2010;93: Butts S, Riethman H, Ratcliffe S, Shaunik A, Coutifaris C, Barnhart K. Correlation of telomere length and telomerase activity with occult ovarian insufficiency. J Clin Endocrinol Metab 2009;94: Requena A, Herrero J, Landeras J, Navarro E, Neyro JL, Salvador C, et al. Use of letrozole in assisted reproduction: a systematic review and meta-analysis. Hum Reprod Update 2008;14: VOL. 97 NO. 4 / APRIL 2012

Oocyte Freezing and Ovarian Tissue Cryopreservation:

Oocyte Freezing and Ovarian Tissue Cryopreservation: Comparing Results of These Two Methods in One Program Dr. César Díaz García cesar.diaz@ivi.uk IVI London 83, Wimpole St. London, UK London Conflict