Ovarian stimulation in cancer patients
2013; Elsevier BV; Volume: 99; Issue: 6 Linguagem: Inglês
10.1016/j.fertnstert.2013.03.029
ISSN1556-5653
AutoresHakan Çakmak, Mitchell P. Rosen,
Tópico(s)Sperm and Testicular Function
ResumoThe patients referred for fertility preservation owing to a malignant disease do not represent the typical population of subfertile patients treated in IVF units. Cancer may affect multiple tissues throughout the body and can result in a variety of complications during controlled ovarian stimulation. Determination of the controlled ovarian stimulation protocol and gonadotropin dose for oocyte/embryo cryopreservation requires an individualized assessment. This review highlights the new protocols that are emerging to reduce time constraints and emphasizes management considerations to decrease complications. The patients referred for fertility preservation owing to a malignant disease do not represent the typical population of subfertile patients treated in IVF units. Cancer may affect multiple tissues throughout the body and can result in a variety of complications during controlled ovarian stimulation. Determination of the controlled ovarian stimulation protocol and gonadotropin dose for oocyte/embryo cryopreservation requires an individualized assessment. This review highlights the new protocols that are emerging to reduce time constraints and emphasizes management considerations to decrease complications. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/cakmakh-ovarian-stimulation-cancer-fertility-preservation/Cancer is not uncommon and no longer considered to be an incurable disease among reproductive-age women. More than 790,000 new female cancer cases were estimated to be diagnosed in 2012 in the United States (1American Cancer SocietyCancer facts and figures 2012. American Cancer Society, Atlanta2012http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2012Google Scholar). Approximately 10% of female cancer cases occur under the age of 45 years (2Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, et al. (eds.). SEER cancer statistics review, 1975–2009 (vintage 2009 populations). Bethesda, MD: National Cancer Institute. Available at: http://seer.cancer.gov/csr/1975_2009_pops09/. Accessed December 16, 2012.Google Scholar). Over the past three decades, there has been a remarkable improvement in the survival rates owing to progress in diagnosing certain cancers at an earlier stage and improvements in treatment (2Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, et al. (eds.). SEER cancer statistics review, 1975–2009 (vintage 2009 populations). Bethesda, MD: National Cancer Institute. Available at: http://seer.cancer.gov/csr/1975_2009_pops09/. Accessed December 16, 2012.Google Scholar). From 2002 to 2012, 83% of women younger than 45 years diagnosed with cancer survived (2Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, et al. (eds.). SEER cancer statistics review, 1975–2009 (vintage 2009 populations). Bethesda, MD: National Cancer Institute. Available at: http://seer.cancer.gov/csr/1975_2009_pops09/. Accessed December 16, 2012.Google Scholar). As a consequence of the increase in the number of patients surviving cancer, greater attention has been focused on the delayed effects of cancer treatments on the quality of future life of the survivor (3Letourneau J.M. Ebbel E.E. Katz P.P. Katz A. Ai W.Z. Chien A.J. et al.Pretreatment fertility counseling and fertility preservation improve quality of life in reproductive age women with cancer.Cancer. 2012; 118: 1710-1717Crossref PubMed Scopus (355) Google Scholar, 4Letourneau J.M. Melisko M.E. Cedars M.I. Rosen M.P. A changing perspective: improving access to fertility preservation.Nat Rev Clin Oncol. 2011; 8: 56-60Crossref PubMed Scopus (38) Google Scholar).The treatment for most of the cancer types in reproductive-age women involves either removal of the reproductive organs or cytotoxic treatment (chemotherapy and/or radiotherapy) that may partially or definitively affect reproductive function (5Rodriguez-Wallberg K.A. Oktay K. Options on fertility preservation in female cancer patients.Cancer Treat Rev. 2012; 38: 354-361Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). The ovary is particularly sensitive to the adverse effects of cancer treatments because of the set number of follicles present in the postnatal ovary (5Rodriguez-Wallberg K.A. Oktay K. Options on fertility preservation in female cancer patients.Cancer Treat Rev. 2012; 38: 354-361Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). Reproductive lifespan is determined by the follicle pool, and therefore, cancer treatments that cause follicular depletion accelerate the onset of menopause (6Sklar C.A. Mertens A.C. Mitby P. Whitton J. Stovall M. Kasper C. et al.Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study.J Natl Cancer Inst. 2006; 98: 890-896Crossref PubMed Scopus (415) Google Scholar). The irreversible gonadotoxic effects of some of the chemotherapeutic agents are well documented, particularly for alkylating agents (e.g., cyclophosphamide, busulfan, and ifosfamide), which are common components of chemotherapy for breast cancer, lymphomas, leukemia, and sarcomas (7Maltaris T. Seufert R. Fischl F. Schaffrath M. Pollow K. Koelbl H. et al.The effect of cancer treatment on female fertility and strategies for preserving fertility.Eur J Obstet Gynecol Reprod Biol. 2007; 130: 148-155Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 8Letourneau J.M. Ebbel E.E. Katz P.P. Oktay K.H. McCulloch C.E. Ai W.Z. et al.Acute ovarian failure underestimates age-specific reproductive impairment for young women undergoing chemotherapy for cancer.Cancer. 2012; 118: 1933-1939Crossref PubMed Scopus (154) Google Scholar). Pelvic radiation therapy is also known to cause follicular destruction, and exposure to 5–10 Gy pelvic radiation appears to be toxic to oocytes, resulting in premature ovarian insufficiency in many women (5Rodriguez-Wallberg K.A. Oktay K. Options on fertility preservation in female cancer patients.Cancer Treat Rev. 2012; 38: 354-361Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar). The risk of ovarian failure following cancer therapy appears to be dose related, and the effect depends on age and ovarian reserve at the time of treatment (9Meirow D. Nugent D. The effects of radiotherapy and chemotherapy on female reproduction.Hum Reprod Update. 2001; 7: 535-543Crossref PubMed Scopus (657) Google Scholar).Early loss of ovarian function not only puts the patients at risk for menopause-related complications at a very young age, but is also associated with loss of fertility (8Letourneau J.M. Ebbel E.E. Katz P.P. Oktay K.H. McCulloch C.E. Ai W.Z. et al.Acute ovarian failure underestimates age-specific reproductive impairment for young women undergoing chemotherapy for cancer.Cancer. 2012; 118: 1933-1939Crossref PubMed Scopus (154) Google Scholar). In addition, women in the United States have been delaying initiation of childbearing to later in life for social and financial reasons. The birth rate for women aged 30–34 years increased from 80.8 births per 1,000 women in 1990 to 96.5 births per 1,000 women in 2011 (10Hamilton B.E. Martin J.A. Ventura S.J. Births: preliminary data for 2011.National vital statistics reports web release. vol. 61, no. 5. National Center for Health Statistics, Hyattsville, MD2012Google Scholar). Similarly, the rate for women aged 35–44 years rose 54% from 1990 to 2011, increasing from 37.2 to 57.5 births per 1,000 women (10Hamilton B.E. Martin J.A. Ventura S.J. Births: preliminary data for 2011.National vital statistics reports web release. vol. 61, no. 5. National Center for Health Statistics, Hyattsville, MD2012Google Scholar). In other words, more women in their 30s to early 40s are attempting to get pregnant for the first time than ever before. Because the incidence of most cancers increases with age and many women wish to conceive using their own oocytes, delayed childbearing results in more female cancer survivors interested in fertility preservation.Multiple strategies have emerged aiming to preserve fertility in women with different types of malignancies. These include embryo and oocyte cryopreservation, cortical and whole ovary cryopreservation, ovarian transplantation, ovarian transposition, and GnRH agonist protection (11Anderson R.A. Wallace W.H. Fertility preservation in girls and young women.Clin Endocrinol (Oxf). 2011; 75: 409-419Crossref PubMed Scopus (62) Google Scholar). Currently, embryo and mature oocyte cryopreservation following in vitro fertilization (IVF) are the only techniques endorsed by the American Society of Reproductive Medicine, and the other methods are still considered to be investigational (12Practice Committee of the American Society for Reproductive MedicineFertility preservation and reproduction in cancer patients.Fertil Steril. 2005; 83: 1622-1628Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar, 13Practice Committee of the American Society for Reproductive MedicineMature oocyte cryopreservation: a guideline.Fertil Steril. 2013; 99: 37-43Abstract Full Text Full Text PDF PubMed Scopus (670) Google Scholar).Controlled ovarian stimulation (COS) for embryo or mature oocyte cryopreservation is the most preferred method for fertility preservation in cancer patients, owing to its higher success rates compared with other, more experimental, technologies (12Practice Committee of the American Society for Reproductive MedicineFertility preservation and reproduction in cancer patients.Fertil Steril. 2005; 83: 1622-1628Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar, 13Practice Committee of the American Society for Reproductive MedicineMature oocyte cryopreservation: a guideline.Fertil Steril. 2013; 99: 37-43Abstract Full Text Full Text PDF PubMed Scopus (670) Google Scholar). Therefore, it should be recommended as long as the patient's medical condition does not preclude safely performing COS or oocyte retrieval and the patient has adequate time to undergo COS and oocyte retrieval (12Practice Committee of the American Society for Reproductive MedicineFertility preservation and reproduction in cancer patients.Fertil Steril. 2005; 83: 1622-1628Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar, 13Practice Committee of the American Society for Reproductive MedicineMature oocyte cryopreservation: a guideline.Fertil Steril. 2013; 99: 37-43Abstract Full Text Full Text PDF PubMed Scopus (670) Google Scholar). To facilitate initiation of ovarian stimulation and avoid unnecessary delay, prompt consultation with a reproductive endocrinologist and coordination of care are necessary after the cancer diagnosis (14Lee S. Ozkavukcu S. Heytens E. Moy F. Oktay K. Value of early referral to fertility preservation in young women with breast cancer.J Clin Oncol. 2010; 28: 4683-4686Crossref PubMed Scopus (108) Google Scholar).The number of oocytes retrieved and their quality are imperative factors predicting the potential efficacy of the fertility preservation procedure. Consequently, information regarding the expected ovarian performance after COS is crucial when consulting with the patient. Therefore, the assessment of ovarian reserve with the use of antral follicle count (AFC) and/or antimüllerian hormone (AMH) before ovarian stimulation is necessary to provide more accurate prediction of ovarian response to COS and to determine the COS protocol and starting gonadotropin dose (15Reddy J. Oktay K. Ovarian stimulation and fertility preservation with the use of aromatase inhibitors in women with breast cancer.Fertil Steril. 2012; 98: 1363-1369Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar).Response to ovarian stimulation in cancer patientsIn cancer patients, both the specific malignancy and the patient's multisystemic condition may have an impact on the response to ovarian stimulation (16Friedler S. Koc O. Gidoni Y. Raziel A. Ron-El R. Ovarian response to stimulation for fertility preservation in women with malignant disease: a systematic review and meta-analysis.Fertil Steril. 2012; 97: 125-133Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). The increased catabolic state, malnutrition, and increased stress hormone levels associated with the malignancy may affect the hypothalamic-gonadal axis and decrease fertility (17Agarwal A. Said T.M. Implications of systemic malignancies on human fertility.Reprod Biomed Online. 2004; 9: 673-679Abstract Full Text PDF PubMed Scopus (42) Google Scholar). Possible adverse association between the presence of a neoplastic process and ovarian reserve or oocyte quality is also suggested (17Agarwal A. Said T.M. Implications of systemic malignancies on human fertility.Reprod Biomed Online. 2004; 9: 673-679Abstract Full Text PDF PubMed Scopus (42) Google Scholar, 18Oktay K. Kim J.Y. Barad D. Babayev S.N. Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks.J Clin Oncol. 2010; 28: 240-244Crossref PubMed Scopus (262) Google Scholar, 19Pal L. Leykin L. Schifren J.L. Isaacson K.B. Chang Y.C. Nikruil N. et al.Malignancy may adversely influence the quality and behaviour of oocytes.Hum Reprod. 1998; 13: 1837-1840Crossref PubMed Scopus (56) Google Scholar). There are mixed reports about how cancer patients respond to the IVF stimulation protocols: some reporting no significant change (20Das M. Shehata F. Moria A. Holzer H. Son W.Y. Tulandi T. Ovarian reserve, response to gonadotropins, and oocyte maturity in women with malignancy.Fertil Steril. 2011; 96: 122-125Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 21Knopman J.M. Noyes N. Talebian S. Krey L.C. Grifo J.A. Licciardi F. Women with cancer undergoing ART for fertility preservation: a cohort study of their response to exogenous gonadotropins.Fertil Steril. 2009; 91: 1476-1478Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 22Robertson A.D. Missmer S.A. Ginsburg E.S. Embryo yield after in vitro fertilization in women undergoing embryo banking for fertility preservation before chemotherapy.Fertil Steril. 2011; 95: 588-591Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar) and others demonstrating worse ovarian response in cancer patients compared with age-matched healthy women (19Pal L. Leykin L. Schifren J.L. Isaacson K.B. Chang Y.C. Nikruil N. et al.Malignancy may adversely influence the quality and behaviour of oocytes.Hum Reprod. 1998; 13: 1837-1840Crossref PubMed Scopus (56) Google Scholar, 23Klock S.C. Zhang J.X. Kazer R.R. Fertility preservation for female cancer patients: early clinical experience.Fertil Steril. 2010; 94: 149-155Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). In a recent meta-analysis conducted on seven retrospective studies, women with malignancies had lower numbers of total oocytes (11.7 ± 7.5 vs. 13.5 ± 8.4) and mature oocytes retrieved (9.0 ± 6.5 vs. 10.8 ± 6.8) after COS for fertility preservation compared with healthy age-matched patients (16Friedler S. Koc O. Gidoni Y. Raziel A. Ron-El R. Ovarian response to stimulation for fertility preservation in women with malignant disease: a systematic review and meta-analysis.Fertil Steril. 2012; 97: 125-133Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). Moreover, the relative risk of poor response leading to cycle cancellation was higher in cancer patients than in the control group (risk ratio 1.32, 95% confidence interval 0.78–2.17) although the observed difference did not reach statistical significance, possibly due to the small size of the groups (16Friedler S. Koc O. Gidoni Y. Raziel A. Ron-El R. Ovarian response to stimulation for fertility preservation in women with malignant disease: a systematic review and meta-analysis.Fertil Steril. 2012; 97: 125-133Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar).BRCA genes play an essential role in double-strand DNA break repair, and their mutations are associated with an increased risk of breast and ovarian cancers (24Ford D. Easton D.F. Peto J. Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence.Am J Hum Genet. 1995; 57: 1457-1462PubMed Google Scholar). In patients with BRCA mutations, oocytes may be more prone to DNA damage, clinically manifesting as diminished ovarian reserve or earlier menopause (25Lin W.T. Beattie M. Chen L. Oktay K. Crawford S.L. Gold E.B. et al.Comparison of age at natural menopause in BRCA1/2 mutation carriers with a non–clinic-based sample of women in northern California.Cancer. 2013 Jan 29; ([Epub ahead of print])https://doi.org/10.1002/cncr.27952Crossref PubMed Scopus (93) Google Scholar). In BRCA mutation–positive breast cancer patients, a low response to ovarian stimulation occurred more frequently than in patients without BRCA mutations (33.3% vs. 3.3%) or in breast cancer patients not tested for their BRCA status (2.9%) (18Oktay K. Kim J.Y. Barad D. Babayev S.N. Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks.J Clin Oncol. 2010; 28: 240-244Crossref PubMed Scopus (262) Google Scholar). Interestingly, all BRCA mutation–positive patients with a low response to ovarian stimulation and requiring higher doses of gonadotropins for their stimulation had BRCA-1 mutations, and a low response was not encountered in women who were positive for only a BRCA-2 mutation (18Oktay K. Kim J.Y. Barad D. Babayev S.N. Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks.J Clin Oncol. 2010; 28: 240-244Crossref PubMed Scopus (262) Google Scholar).None of the studies mentioned above compared the ovarian reserve of cancer patients with healthy age-matched women. In a recent study, ovarian reserve assessed with AMH was found to be significantly lower in patients with lymphoma before chemotherapy compared with healthy control subjects (26Lawrenz B. Fehm T. von Wolff M. Soekler M. Huebner S. Henes J. et al.Reduced pretreatment ovarian reserve in premenopausal female patients with Hodgkin lymphoma or non-Hodgkin-lymphoma—evaluation by using antimüllerian hormone and retrieved oocytes.Fertil Steril. 2012; 98: 141-144Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Moreover, we previously demonstrated that women with cancer before gonadotoxic therapy may have significantly lower AFC compared with healthy women aged 25–40 years (Table 1) (27Ebbel E. Katz A. Kao C.N. Cedars M.I. Rosen M.P. Reproductive aged women with cancer have a lower antral follicle count than expected.Fertil Steril. 2011; 96: S199-S200Abstract Full Text Full Text PDF Google Scholar). This lower AFC in cancer patients may be explained by either accelerated follicle loss or a defect in recruitment of antral follicles owing to disease state. It is well established that AFC correlates directly with number of follicles, number of mature oocytes retrieved, and number of embryos obtained during an IVF cycle (28Frattarelli J.L. Levi A.J. Miller B.T. Segars J.H. A prospective assessment of the predictive value of basal antral follicles in in vitro fertilization cycles.Fertil Steril. 2003; 80: 350-355Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). In our clinical experience, although the number of mature oocytes retrieved and embryos obtained may be lower in cancer patients compared with healthy individuals, they are appropriate for their given AFC. Moreover, their response to the gonadotropins and mature oocyte yield (i.e., number of metaphase II [MII] oocytes/AFC) are similar to those of the healthy women. Therefore, if lower oocyte and embryo numbers in patients with malignancy during an IVF cycle are true, this is not due to poor response to ovarian stimulation, but likely the result of decreased number of available antral follicles to be stimulated.Table 1Comparison of antral follicle count (AFC) between cancer patients and healthy women in different age groups 26Lawrenz B. Fehm T. von Wolff M. Soekler M. Huebner S. Henes J. et al.Reduced pretreatment ovarian reserve in premenopausal female patients with Hodgkin lymphoma or non-Hodgkin-lymphoma—evaluation by using antimüllerian hormone and retrieved oocytes.Fertil Steril. 2012; 98: 141-144Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar.Age (y)Cancer patientsHealthy womenP valuenMedianRangenMedianRange25–3033141–58205204–58<.00131–3547110–54216155–48.00436–404970–40227120–52<.00141–452071–2016161–22.789 Open table in a new tab In conclusion, candidates for fertility preservation because of malignancy, especially BRCA-1 mutation carriers, should be informed that the expected number of oocytes retrieved after COS may be lower compared with healthy patients of similar age. However, more studies are needed to confirm these findings.Gonadotropin dose during ovarian stimulationMaximizing the number of embryos and oocytes cryopreserved during a fertility preservation cycle is extremely important, not only because the patient usually has a single cycle opportunity owing to time constraints, but also to increase the chance of future pregnancies. Using higher doses of gonadotropins can be one of the strategies to increase the embryo and oocyte yield per cycle. In a study comparing a low-dose antagonist IVF protocol (150 IU FSH) and a higher-dose antagonist IVF protocol (>150 UI) in cancer patients, although the number of follicles >17 mm was greater in the higher-dose group, there was no difference in numbers of oocytes (13.3 ± 8.7 vs. 12.3 ± 8.0) or embryos (6.3 ± 4.7 vs. 5.4 ± 3.8) generated between the two groups (29Lee S. Oktay K. Does higher starting dose of FSH stimulation with letrozole improve fertility preservation outcomes in women with breast cancer?.Fertil Steril. 2012; 98: 961-964.e1Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). That study suggests that the use of higher doses of gonadotropins may not necessarily result in higher oocyte/embryo yield consistent with the theory that higher doses of gonadotropins may stimulate the recruitment of chromosomally abnormal or incompetent oocytes (30Baart E.B. Martini E. Eijkemans M.J. Van Opstal D. Beckers N.G. Verhoeff A. et al.Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial.Hum Reprod. 2007; 22: 980-988Crossref PubMed Scopus (416) Google Scholar). However, in patients with decreased ovarian reserve as assessed with the use of AFC and/or AMH, higher doses of gonadotropins may be required.Ovarian stimulation protocolsConventional Controlled Ovarian StimulationThe choice of the specific COS protocol is generally determined based on the policy of preferences in each IVF center and influenced by the time available until the initiation of radio/chemotherapy. Although multiple different COS protocols are used, the majority of patients are treated with a GnRH antagonist–based protocol, which likely allows the shortest deferral of the initiation of radio/chemotherapy. To date, there are no studies comparing agonist and antagonist protocols in women with cancer.Traditional ovarian preparation for IVF requires 9–14 days of ovarian stimulation with exogenous gonadotropins, preceded by ovarian suppression with GnRH agonists for ∼2 weeks to prevent premature ovulation. Because GnRH agonist is initiated in the luteal phase of the cycle, this may add up to 3 additional weeks to the process, depending on when the patient presents for treatment.The development of GnRH antagonists has significantly decreased the interval from patient presentation to embryo/oocyte cryopreservation (31McLaren J.F. Bates G.W. Fertility preservation in women of reproductive age with cancer.Am J Obstet Gynecol. 2012; 207: 455-462Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). In contrast to GnRH agonists, GnRH antagonists immediately suppress pituitary release of FSH and LH and do not require the 10–14 days of administration before gonadotropin initiation. GnRH antagonists are initiated to prevent premature LH surge when the size of the lead follicle reaches 12–14 mm at approximately day 6 of gonadotropin stimulation which begins on day 2–3 of a menstrual cycle (Fig. 1A). This approach still requires awaiting menses before initiating gonadotropins, but it decreases the interval to oocyte retrieval compared to traditional IVF stimulation protocols.The use of GnRH antagonists during the preceding luteal phase was explored originally for cancer patients and then for poor IVF responders as a method to improve ovarian stimulation by inducing corpus luteum breakdown and synchronizing the development of the next wave of follicles (32Anderson R.A. Kinniburgh D. Baird D.T. Preliminary experience of the use of a gonadotrophin-releasing hormone antagonist in ovulation induction/in-vitro fertilization prior to cancer treatment.Hum Reprod. 1999; 14: 2665-2668Crossref PubMed Scopus (50) Google Scholar, 33Humaidan P. Bungum L. Bungum M. Hald F. Agerholm I. Blaabjerg J. et al.Reproductive outcome using a GnRH antagonist (cetrorelix) for luteolysis and follicular synchronization in poor responder IVF/ICSI patients treated with a flexible GnRH antagonist protocol.Reprod Biomed Online. 2005; 11: 679-684Abstract Full Text PDF PubMed Scopus (38) Google Scholar). For cancer patients, the idea of administering GnRH antagonists in the luteal phase was driven more by minimizing potential delays for cancer treatment (32Anderson R.A. Kinniburgh D. Baird D.T. Preliminary experience of the use of a gonadotrophin-releasing hormone antagonist in ovulation induction/in-vitro fertilization prior to cancer treatment.Hum Reprod. 1999; 14: 2665-2668Crossref PubMed Scopus (50) Google Scholar). If a GnRH antagonist (e.g., single dose of 3 mg cetrorelix subcutaneously) is given during the midluteal phase, menses ensues a few days later (32Anderson R.A. Kinniburgh D. Baird D.T. Preliminary experience of the use of a gonadotrophin-releasing hormone antagonist in ovulation induction/in-vitro fertilization prior to cancer treatment.Hum Reprod. 1999; 14: 2665-2668Crossref PubMed Scopus (50) Google Scholar, 33Humaidan P. Bungum L. Bungum M. Hald F. Agerholm I. Blaabjerg J. et al.Reproductive outcome using a GnRH antagonist (cetrorelix) for luteolysis and follicular synchronization in poor responder IVF/ICSI patients treated with a flexible GnRH antagonist protocol.Reprod Biomed Online. 2005; 11: 679-684Abstract Full Text PDF PubMed Scopus (38) Google Scholar) (Fig. 1B). As a result, ovarian stimulation would be initiated more quickly and a GnRH antagonist would be restarted in a standard fashion, when the lead follicle is at 12–14 mm to prevent premature LH surge (33Humaidan P. Bungum L. Bungum M. Hald F. Agerholm I. Blaabjerg J. et al.Reproductive outcome using a GnRH antagonist (cetrorelix) for luteolysis and follicular synchronization in poor responder IVF/ICSI patients treated with a flexible GnRH antagonist protocol.Reprod Biomed Online. 2005; 11: 679-684Abstract Full Text PDF PubMed Scopus (38) Google Scholar).Random-Start Controlled Ovarian HyperstimulationConventionally, ovarian stimulation for oocyte/embryo cryopreservation is initiated at the beginning of the follicular phase with the idea that this optimizes clinical outcomes; it may require 2–6 weeks depending on the woman's menstrual cycle phase at the time of planning the treatment. Adhering to this convention may result in either significant delay of cancer treatments or forgoing of fertility preservation owing to time constraints. For cases not desirable to wait for the next menstrual period to start a stimulation protocol owing to the urgency of the cancer treatment, random-start stimulation protocols have been proposed (34Cakmak H. Zamah A.M. Katz A. Cedars M.I. Rosen M.P. Effective method for emergency fertility preservation: random-start controlled ovarian hyperstimulation.Fertil Steril. 2012; 98: S170Abstract Full Text Full Text PDF Google Scholar, 35Sonmezer M. Turkcuoglu I. Coskun U. Oktay K. Random-start controlled ovarian hyperstimulation for emergency fertility preservation in letrozole cycles.Fertil Steril. 2011; 95: 2125.e9-2125.e11Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 36von Wolff M. Thaler C.J. Frambach T. Zeeb C. Lawrenz B. Popovici R.M. et al.Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase.Fertil Steril. 2009; 92: 1360-1365Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar).In a small prospective multicenter study (n = 40), a novel protocol for cancer patients that initiated ovarian stimulation during the luteal phase of the menstrual cycle was described (36von Wolff M. Thaler C.J. Frambach T. Zeeb C. Lawrenz B. Popovici R.M. et al.Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase.Fertil Steril. 2009; 92: 1360-1365Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar). Cancer patients in the luteal phase were started on GnRH antagonists to down-regulate LH and initiate luteolysis. Simultaneously, follicular stimulation was initiated with recombinant FSH only, thus avoiding exogenous LH activity which might prevent luteolysis. Compared with cancer patients stimulated during the follicular phase (n = 28) with either a short "flare-up" protocol or an antagonist protocol, the luteal-phase group (n = 12) had similar number of aspirated oocytes, number of MII
Referência(s)