/ /

  • linkedin
  • Increase Font
  • Sharebar

    Preserving fertility in women facing cancer

     

     

     

    In 2012, 790,000 new cases of cancer were diagnosed in women in the United States alone, with more than 10% of cases diagnosed in women of reproductive age (younger than 45).1 With advances in cancer treatment and improved survival rates, issues such as loss of fertility are coming to the forefront. Retrospective studies indicate that 30% to 40% of reproductive-age survivors experience a feeling of loss of control over their reproductive future, are discontent with their current number of children, and are unable to talk openly about their fertility.2

    In a survey of more than 600 young women with early-stage breast cancer, 29% reported that concern about infertility influenced their treatment decisions.3 Hence, the American Society of Reproductive Medicine (ASRM) and the American Society of Clinical Oncology have put forth official guidelines recommending that patients be educated about the effect of cancer treatment on fertility and fertility preservation options.4,5

    Even so, loss of fertility remains an under-represented topic. A retrospective survey of 1041 California women diagnosed with cancer and aged 18 to 40 found that only 60% were counseled by their oncologists about the risk of infertility, and only 5% were referred to reproductive endocrinologists.6 Educated women are more likely to be counseled, and female oncologists with a favorable opinion of fertility preservation are most likely to refer patients.7

    Studies have shown significant discrepancies in referral based on ethnicity, parity, and cancer type.8,9 Given the importance and urgency of fertility issues in this population, we recommend that appropriate patients be referred to experienced reproductive endocrinologists as soon as possible for fertility preservation counseling and treatment. This review describes risks of infertility based on specific cancer treatments and fertility preservation strategies for these women (Table 1).

    Gynecologic malignancies

    Gynecologic malignancies are most often treated with pelvic surgery accompanied by chemotherapy and/or radiation. In 2007, the European Society of Gynecologic Oncology launched the Task Force in Fertility Preservation in Gynecologic Cancer to promote awareness of fertility-sparing strategies
    (Table 2).10

    A radical trachelectomy is a viable option for early-stage cervical cancer. In a prospective study of 212 women who underwent radical vaginal trachelectomies, 66% of women attempting to conceive achieved pregnancy.11 Of those who conceived, 45% reached full term, 25% delivered between 28 and 36 gestational weeks, and 5% delivered before 28 gestational weeks.11

    Although fertility does not appear to be impaired, women opting for trachelectomy should be counseled that preterm delivery is a potential obstetric complication. In tumors <2 cm, the cervical cancer recurrence rate is 2% to 6% after a radical trachelectomy, making it an oncologically acceptable procedure as well.12 The recurrence rate after a modified radical hysterectomy varies from 0.1% to 5% depending on stage, and a recent case-control study of 137 women who underwent vaginal radical trachelectomy matched with radical hysterectomy controls demonstrated a 5-year recurrence-free survival rate of 95% and 100%, respectively.13,14

    For early-stage endometrial cancers, a systematic review of 45 studies including 391 participants with complex atypical hyperplasia or grade 1 adenocarcinoma treated with progestin therapies was conducted. Not surprisingly, endometrial hyperplasia had a significantly higher likelihood of responding to hormonal therapy (66%) than did grade 1 endometrial carcinoma (48%). Reproductive outcomes were similar, with 41.2% of those with hyperplasia and 34.8% with carcinoma conceiving, resulting in 117 live births.15

    In the case of ovarian malignancy, a conservative surgical approach to borderline ovarian tumors does not appear to affect survival. However, conservative surgery should be reserved for cases of stage 1A grade 1 epithelial ovarian cancer after adequate staging with careful follow-up.16

    All these options underscore the need for gynecologic oncologists to work in conjunction with reproductive endocrinologists to determine the applicability of fertility-sparing approaches and to counsel patients regarding their future fertility potential.

     

    Radiation therapy

    Total-body irradiation and pelvic or whole-abdomen radiation > 6 Gy in adult women pose a high risk of amenorrhea and ovarian failure.17 Ovaries of pre- and postpubescent girls are likely to tolerate a higher dose of radiation due to a more robust ovarian reserve.17 Specific techniques for preventing radiation damage to the ovaries include pelvic shielding and ovarian transposition, in addition to embryo and oocyte cryopreservation (Table 1).

    Ovarian transposition is a surgical repositioning of the ovaries away from the radiation field, performed by either laparotomy or laparoscopy (Figure 1). Techniques have been described to relocate the ovaries to the paracolic gutters, behind the uterus, or to anterolateral positions above the umbilicus.18 A wide variation in the reduction of risk of ovarian failure exists after ovarian transposition (16%–90%) due to altered ovarian blood flow and scattered radiation.17,19 Repositioning of the ovaries or in vitro fertilization (IVF) may be necessary to achieve pregnancy.19,20

     

    Irradiation of the uterus also has a negative effect on pregnancy outcomes. Cohorts of childhood cancer survivors have demonstrated that women who received pelvic radiation were at a higher risk of preterm labor, miscarriage, and low-birth-weight infants.21-23 This may be due to reduced uterine volume following direct uterine irradiation.24

     

    Chemotherapy

    Most chemotherapeutic agents are gonadotoxic, with alkylating agents such as cyclophosphamide and ifosfamide posing the highest risk of amenorrhea and ovarian failure.17 Strategies for fertility preservation prior to chemotherapy depend on a patient’s age, the urgency of cancer treatment, and the availability of a sperm source (Table 2).

    Embryo and oocyte cryopreservation are the 2 established methods of fertility preservation offered through assisted reproductive technology (ART). For patients in whom these methods are not appropriate, experimental procedures such as in vitro maturation (IVM), ovarian tissue cryopreservation, and the use of gonadotropin-releasing hormone (GnRH) agonists may be considered.

    Established methods of fertility preservation

    Embryo cryopreservation – Embryo cryopreservation is the gold standard in fertility preservation when partner or donor sperm is available. This process requires 10–14 days of ovarian stimulation with daily gonadotropin injections, accompanied by frequent visits for ultrasound monitoring and blood work. Mature oocytes are harvested via transvaginal needle aspiration. The oocytes are fertilized with partner or donor sperm and cryopreserved after 3 or 5 days.

    Oocyte cryopreservation – Mature oocyte cryopreservation is an alternative option for women who do not have partners or who are unwilling to use donor sperm. Patients undergo the same process as embryo cryopreservation except oocytes are cryopreserved immediately instead of being fertilized by sperm.

    Until recently, oocyte cryopreservation was considered an experimental procedure. However, in October 2012, ASRM published an official guideline stating that mature oocyte cryopreservation should no longer be considered experimental and can be recommended with appropriate counseling to patients receiving gonadotoxic therapies for cancer.25 This new recommendation was based on significantly improved outcomes with the use of vitrified oocytes. Vitrification is a technique in which freezing occurs very rapidly with liquid nitrogen and the oocyte is solidified into a glass-like state.

    Slow freezing, an older method of oocyte cryopreservation, was carried out at a very slow rate to prevent ice formation and damage to the oocytes. Small randomized controlled trials have demonstrated improved pregnancy success rates with vitrified oocytes compared to slow-freeze oocytes and pregnancy success rates that are comparable between fresh oocytes and vitrified oocytes in women of younger reproductive age (<37 years).26,27

    Vitrified oocytes lead to an overall clinical pregnancy rate of 4.6%–12% per oocyte. Although data are limited, there appears to be no increase in chromosomal abnormalities or birth defects in infants from cryopreserved oocytes compared to offspring from conventional IVF or in the general population.28

     

    Ovarian stimulation concerns

    Previously, conventional ovarian stimulation translated to a 2- to 6-week delay in cancer treatment, depending on when the patient presented in relation to her menstrual cycle. Patients with cancer may not be willing to accept this delay or the exposure to hormone injections. Conventional protocols have been modified to address these concerns. Studies have demonstrated that a random-start protocol, in which urgent ovarian stimulation is initiated regardless of menstrual cycle phase, can be as effective as conventional stimulation.29 The random-start protocol allows patients to undergo ovarian stimulation at any point in the menstrual cycle, requiring at most a 2-week delay in cancer treatment.

    For patients with hormone-sensitive tumors such as breast tumors, protocols have been developed to decrease estrogen exposure using aromatase inhibitors such as letrozole, in addition to gonadotropins. Stimulation protocols using letrozole successfully suppress estradiol levels without an adverse effect on oocyte retrieval and embryo formation and do not appear to increase the short-term risk of breast cancer recurrence.30, 31

    Experimental methods of fertility preservation

    IVM– IVM is the process of maturing immature oocytes in the laboratory.32 After retrieval, immature oocytes are cultured in the laboratory to achieve both nuclear and cytoplasmic maturation and are then cryopreserved. Immature oocytes can be collected from the ovaries during both the follicular and luteal phases. Because no gonadotropin injections (or very few) are used and the procedure can be done expeditiously, this option may be attractive to patients who need urgent chemotherapy or who do not want to be exposed to exogenous hormones.33

    This method has been primarily used in women with polycystic ovary syndrome as a means to reduce ovarian hyperstimulation syndrome. However, studies demonstrate lower implantation rates, clinical pregnancy rates, and live birth rates compared to conventional IVF, limiting the widespread utility of IVM.34-36 Despite this, preliminary studies provide reassuring data suggesting no increased risk of adverse obstetric or perinatal outcomes in infants conceived through IVM versus by conventional IVF.37-39

    Ovarian tissue cryopreservation – Ovarian tissue cryopreservation is another experimental method for fertility preservation and is the only option for prepubescent girls. This procedure involves laparoscopic surgery to obtain ovarian cortical biopsies containing healthy follicles. The biopsies are cryopreserved and then reimplanted after the patient is disease-free. Orthotopic reimplantation occurs in the pelvic cavity, while heterotopic reimplantation occurs in an area outside the pelvic cavity, such as the forearm.

    To date, 24 live births have resulted from orthotopic reimplantation of cryopreserved ovarian tissue, with >50% of women conceiving naturally.40 One concern with this procedure is the potential for reintroducing cancer cells, which could lead to recurrence of malignancy after reimplantation.41 Loss of >50% primordial follicles due to tissue ischemia during reimplantation is another issue that limits use of ovarian tissue cryopreservation as a mainstream option for fertility preservation.

    GnRH agonist for ovarian suppression – The efficacy of GnRH agonists during chemotherapy for ovarian suppression is debatable. Primordial follicles do not have gonadotropin receptors, so it is biologically implausible that GnRH agonists prevent primordial follicles from undergoing follicular recruitment and being susceptible to chemotherapy. Other possible mechanisms include a decrease in perfusion and ovarian exposure to chemotherapy, a gonadotropin-independent effect, or up-regulation of ovarian antiapoptotic molecules.

    Despite concurrent GnRH agonist administration, ovarian reserve markers—such as anti-Mullerian hormone and antral follicle count—can be undetectable 12 months after chemotherapy.42

    Some trials have suggested that concurrent administration of a GnRH agonist with chemotherapy in breast cancer patients decreases risk of chemotherapy-induced amenorrhea, whereas other studies have not observed this benefit after adjusting for age, estrogen receptor status, and treatment regimen.43,44 Return of menses does not equate to fertility and none of these studies measured the end outcome of fertility or pregnancy rate.4 Thus, at this time, GnRH agonist administration is not considered an effective method of fertility preservation.5

    Third-party reproduction – Third-party reproduction, including the use of oocyte donors and gestational carriers, is an additional option for cancer survivors. A patient who experiences ovarian failure after chemotherapy can still conceive and carry a pregnancy using oocytes from an anonymous donor or a directed donor.

    A gestational carrier may be used if a patient had a hysterectomy as part of her cancer treatment or her uterine capacity is questionable after pelvic radiation. Some patients with a history of hormone-sensitive tumors, such as breast tumors, may opt for gestational carriers to avoid exposure to pregnancy hormones.

    Summary

    Fertility preservation in reproductive-age women with cancer remains an important but under-represented topic. Specific fertility preservation strategies exist for women facing gynecologic surgery, pelvic radiation, and/or chemotherapy. Recent advances in the field of ART have made oocyte cryopreservation, in addition to embryo cryopreservation, an established and accepted option.

    Optimization of investigational methods such as IVM and ovarian tissue cryopreservation is the goal of researchers in this field in order to better meet the needs of all women with cancer.

     

    References

    1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. Cancer J Clin. 2012:62(1):10–29.

    2. Wenzel L, Dogan-Ates A, Habbal R, et al. Defining and measuring reproductive concerns of female cancer survivors. J Natl Cancer Inst. 2005;(34):94–98.

    3. Partridge AH, Gelber S, Peppercorn J, et al. Web-based survey of fertility issues in young women with breast cancer. J Clin Oncol. 2004;22(20):4174–4183.

    4. Ethics Committee of the American Society for Reproductive M. Fertility preservation and reproduction in cancer patients. Fertil Steril. 2005;83(6):1622–1628.

    5. Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(19):2500–2510.

    6. Letourneau JM, Smith JF, Ebbel EE, et al. Racial, socioeconomic, and demographic disparities in access to fertility preservation in young women diagnosed with cancer. Cancer. 2012;118(18):4579–4588.

    7. Quinn GP, Vadaparampil ST, Lee JH, et al. Physician referral for fertility preservation in oncology patients: a national study of practice behaviors. J Clin Oncol. 2009;27(35):5952–5957.

    8. Kohler TS, Kondapalli LA, Shah A, Chan S, Woodruff TK, Brannigan RE. Results from the survey for preservation of adolescent reproduction (SPARE) study: gender disparity in delivery of fertility preservation message to adolescents with cancer. J Assist Reprod Genet. 2011;28(3):269–277.

    9. Goodman LR, Balthazar U, Kim J, Mersereau JE. Trends of socioeconomic disparities in referral patterns for fertility preservation consultation. Hum Reprod. 2012;27(7):2076–2081.

    10. Denschlag D, Reed NS, Rodolakis A. Fertility-sparing approaches in gynecologic cancers: a review of ESGO task force activities. Curr Oncol Rep. 2012;14(6):535–538.

    11. Speiser D, Mangler M, Kohler C, et al. Fertility outcome after radical vaginal trachelectomy: a prospective study of 212 patients. Int J Gynecol Cancer. 2011;21(9): 1635–1639.

    12. Schneider A, Erdemoglu E, Chiantera V, et al. Clinical recommendation radical trachelectomy for fertility preservation in patients with early-stage cervical cancer. Int J Gynecol Cancer. 2012;22(4):659–666.

    13. Suprasert P, Srisomboon J, Charoenkwan K, et al. Twelve years experience with radical hysterectomy and pelvic lymphadenectomy in early stage cervical cancer. J Obstet Gynaecol. 2010;30:294-8.

    14. Beiner ME, Hauspy J, Rosen B, et al. Radical vaginal trachelectomy vs. radical hysterectomy for small early stage cervical cancer: a matched case-control study. Gynecol Oncol. 2008;110:168-71.

    15. Gunderson CC, Fader AN, Carson KA, Bristow RE. Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review. Gynecol Oncol. 2012;125(2):477–482.

    16. Morice P, Denschlag D, Rodolakis A, et al. Recommendations of the Fertility Task Force of the European Society of Gynecologic Oncology about the conservative management of ovarian malignant tumors. Int J Gynecol Cancer. 2011;21(5):951–963.

    17. Rodriguez-Wallberg KA, Oktay K. Options on fertility preservation in female cancer patients. Cancer Treat Rev. 2012;38(5):354–361.

    18. Clough KB, Goffinet F, Labib A, et al. Laparoscopic unilateral ovarian transposition prior to irradiation: prospective study of 20 cases. Cancer. 1996;77(12):2638–2645.

    19. Morice P, Thiam-Ba R, Castaigne D, et al. Fertility results after ovarian transposition for pelvic m ignancies treated by external irradiation or brachytherapy. Hum Reprod. 1998; 13(3):660–663.

    20. Williams RS, Littell RD, Mendenhall NP. Laparoscopic oophoropexy and ovarian function in the treatment of Hodgkin disease. Cancer. 1999;86(10):2138–2142.

    21. Green DM, Whitton JA, Stovall M, et al. Pregnancy outcome of female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. AmJ Obstet Gynecol. 2002;187(4):1070–1080.

    22. Green DM, Sklar CA, Boice JD, Jr., et al. Ovarian failure and reproductive outcomes after childhood cancer treatment: results from the Childhood Cancer Survivor Study. J Clin Oncol. 2009;27(14):2374–2381.

    23. Signorello LB, Cohen SS, Bosetti C, et al. Female survivors of childhood cancer: preterm birth and low birth weight among t heir children. Gynecol Oncol. J Natl Cancer Inst. 2006;98(20):1453–1461.

    24. Larsen EC, Schmiegelow K, Rechnitzer C, Loft A, Muller J, Andersen AN. Radiotherapy at a young age reduces uterine volume of childhood cancer survivors. Acta Obstet Gynecol Scand. 2004,83(1):96–102.

    25. Practice Committees of American Society for Reproductive M, Society for Assisted Reproductive T. Mature oocyte cryopreservation: a guideline. Fertil Steril. 2013;99(1):37–43.

    26. Smith GD, Serafini PC, Fioravanti J, et al. Prospective randomized comparison of human oocyte cryopreservation with slow-rate freezing or vitrification. Fertil Steril. 2010;94(6):2088–2095.

    27. Cobo A, Meseguer M, Remohi J, Pellicer A. Use of cryo-banked oocytes in an ovum donation programme: a prospective, randomized, controlled, clinical trial. Hum Reprod. 2010;25(9):2239–2246.

    28. Noyes N, Porcu E, Borini A. Over 900 oocyte cryopreservation babies born with no apparent increase in congenital anomalies. Reprod Biomed Online. 2009;18(6):769–776.

    29. Cakmak H, Katz A, Cedars MI, Rosen MP. Effective method for emergency fertility preservation: random-start controlled ovarian stimulation. Fertil Steril. 2013. [Epub ahead of print].

    30. Oktay K, Hourvitz A, Sahin G, et al. Letrozole reduces estrogen and gonadotropin exposure in women with breast cancer undergoing ovarian stimulation before chemotherapy. J Clin Endocrinol Metab. 2006;91(10):3885–3890.

    31. Azim AA, Costantini-Ferrando M, Oktay K. Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: a prospective controlled study. J Clin Oncol. 2008;26(16):2630–2635.

    32. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. In vitro maturation: a committee opinion. Fertil Steril. 2013;99(3):663–666.

    33. Chian RC, Uzelac PS, Nargund G. In vitro maturation of human immature oocytes for fertility preservation. Fertil Steril. 2013;99(5):1173–1181.

    34. Gremeau AS, Andreadis N, Fatum M, et al. In vitro maturation or in vitro fertilization for women with polycystic ovaries? A case-control study of 194 treatment cycles. Fertil Steril. 2012;98(2):355–360.

    35. Child TJ, Phillips SJ, Abdul-Jalil AK, Gulekli B, Tan SL. A comparison of in vitro maturation and in vitro fertilization for women with polycystic ovaries. Obstet Gynecol. 2002;100(4):665–670.

    36. Fadini R, Mignini Renzini M, Dal Canto M, et al. Oocyte in vitro maturation in normo-ovulatory women. Fertil Steril. 2013;99(5):1162–1169.

    37. Soderstrom-Anttila V, Salokorpi T, Pihlaja M, Serenius-Sirve S, Suikkari AM. Obstetric and perinatal outcome and preliminary results of development of children born after in vitro maturation of oocytes. Hum Reprod. 2006;21(6):1508–1513.

    38. Buckett WM, Chian RC, Holzer H, Dean N, Usher R, Tan SL. Obstetric outcomes and congenital abnormalities after in vitro maturation, in vitro fertilization, and intracytoplasmic sperm injection. Obstet Gynecol. 2007;110(4):885–891.

    39. Fadini R, Mignini Renzini M, Guarnieri T, et al. Comparison of the obstetric and perinatal outcomes of children conceived from in vitro or in vivo matured oocytes in in vitro maturation treatments with births from conventional ICSI cycles. Hum Reprod. 2012;27(12):3601–3608.

    40. Donnez J, Dolmans MM, Pellicer A, et al. Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue: a review of 60 cases of reimplantation. Fertil Steril. 2013;99(6):1503–1513.

    41. Dolmans MM, Luyckx V, Donnez J, Andersen CY, Greve T. Risk of transferring malignant cells with transplanted frozen-thawed ovarian tissue. Fertil Steril. 2013;99(6): 1514–1522.

    42. Behringer K, Wildt L, Mueller H, et al. No protection of the ovarian follicle pool with the use of GnRH-analogues or oral contraceptives in young women treated with escalated BEACOPP for advanced-stage Hodgkin lymphoma. Final results of a phase II trial from the German Hodgkin Study Group. Ann Oncol. 2010;21(10):2052–2060.

    43. Del Mastro L, Boni L, Michelotti A, et al. Effect of the gonadotropin-releasing hormone analogue triptorelin on the occurrence of chemotherapy-induced early menopause in premenopausal women with breast cancer: a randomized trial. JAMA. 2011;306(3):269–276.

    44. Munster PN, Moore AP, Ismail-Khan R, et al. Randomized trial using gonadotropin-releasing hormone agonist triptorelin for the preservation of ovarian function during (neo)adjuvant chemotherapy for breast cancer. J Clin Oncol. 2012;30(5):533–538.

    45. Letourneau JM, Ebbel EE, Katz PP, et al. Acute ovarian failure underestimates age-specific reproductive impairment for young women undergoing chemotherapy for cancer. Cancer. 2012;118(7):1933–1939.

    Erica T. Wang, MD, MAS
    Dr. Wang is an assistant professor at Cedars-Sinai Medical Center and the David Geffen School of Medicine at the University of ...
    Margareta D. Pisarska, MD
    Dr. Pisarska is Director, Division of Reproductive Endocrinology and Infertility, Director, Center for Fertility and Reproductive ...

    0 Comments

    You must be signed in to leave a comment. Registering is fast and free!

    All comments must follow the ModernMedicine Network community rules and terms of use, and will be moderated. ModernMedicine reserves the right to use the comments we receive, in whole or in part,in any medium. See also the Terms of Use, Privacy Policy and Community FAQ.

    • No comments available

    Poll

    Latest Tweets Follow