Fertility preservation in reproductive-age women facing gonadotoxic treatments

Practice Guideline

Fertility preservation in reproductive-age women facing gonadotoxic treatments


J. Roberts, MD*, R. Ronn, MD, N. Tallon, MB BCh BAO*, H. Holzer, MD
*Pacific Centre for Reproductive Medicine, Burnaby, BC;, Department of Obstetrics and Gynecology, Queen’s University, Kingston, ON;, McGill University Health Centre, Reproductive Centre, and Department of Obstetrics and Gynecology, McGill University, Montreal, QC..



doi: http://dx.doi.org/10.3747/co.22.2334


ABSTRACT

Background

Advancements in the treatments for cancer and autoimmune and other hematologic conditions continue to improve survival and cure rates. Despite those changes, various gonadotoxic agents and other treatments can still compromise the future fertility of many women. Progress in medical and surgical reproductive technologies has helped to offset the reproductive consequences of the use of gonadotoxic therapies, and allows for future fertility and normal pregnancy.

Methods

A review of the literature was performed to outline the pathophysiology of gonadotoxicity from various treatments. The success of fertility preservation, fertility sparing, and cryopreservation options are reviewed. Barriers and facilitators to referral and oncofertility treatment in Canada are also outlined.

Results

According to the quality of the evidence, recommendations are made for fertility assessment, patient referral, cryopreservation, and other assisted reproductive technologies.

Conclusions

To ensure ongoing fertility in women undergoing gonadotoxic treatments, assisted reproductive technologies can be combined with a multidisciplinary approach to patient assessment and referral.

KEYWORDS: Oncofertility, fertility preservation, cryopreservation, gonadotoxicity, young adults, adolescents

INTRODUCTION

This guideline is based on currently available evidence in what is often a rapidly advancing field of study. Recommendations might not reflect emerging evidence and are subject to change. Clinical guidelines are intended as an aid to—not a replacement for—clinical judgment. Clinical guidelines neither prevent clinicians from exercising their freedom in good clinical practice, nor relieve them of responsibility to make appropriate decisions based on their own knowledge and experience.

Reproductive Challenges for Young Women Undergoing Gonadotoxic Treatments

Modern cancer treatments for young women have improved cure rates, but more often than not the price paid for survival is the loss of reproductive function from gonadal toxicity. High-dose alkylating agents and ionizing radiation have well-recognized gonadotoxicity, inducing sterility in a high proportion of patients.

Breast cancer affects more than 24,000 Canadian women annually. Of those women, 15% are of reproductive age, making breast cancer the most common malignancy in that age group. Those women also represent the bulk of referrals to assisted reproductive technology facilities for fertility preservation1. Other cancers seen in young women include hematologic (lymphoma and leukemia), endometrial, and cervical cancers. Less commonly, patients with autoimmune disorders such as systemic lupus erythematosus and hematologic conditions will require chemotherapeutic agents for medical management. Gonadal function and fertility outcomes have improved greatly with the newer regimens, but patients and physicians alike have to be aware of the deleterious effects that such treatments have on reproduction.

Management of young woman with cancer presents several unique medical and social challenges. In general, these patients are ill-prepared for the diagnosis of cancer and the reality of their own mortality. With a limited understanding of assisted reproductive technologies or even basic fertility issues, patients are unlikely to seek medical advice about fertility preservation. Breast cancer patients less than 40 years of age are also confronted with more aggressive tumours and reduced disease-free survival24. Combination chemotherapy regimens for breast cancer are delivering ever-increasing rates of 5-year survival in early-stage disease, and further reductions in mortality are achieved with the addition of adjuvant hormonal therapies for patients with estrogen receptor–positive tumours5. However, given the improved survival with tumours of all types and at all stages, the need for adequate fertility counselling and a multidisciplinary team approach for these patients has never been greater6. Patients facing potentially sterilizing chemotherapy and radiotherapy can now benefit from recent advances in cryopreservation techniques that allow for the banking of oocytes, embryos, and ovarian tissue without compromising survival.

In this Canadian Fertility and Andrology Society guideline, we outline the current understanding of the pathophysiology of gonadotoxicity from cancer treatments, the methods to minimize the resulting damage, and the use of medical and surgical reproductive technologies to allow for future fertility and pregnancy. Evidence is graded as outlined in the report of the Canadian Task Force on Preventive Health Care (Table i).

TABLE I Quality of evidence assessment and classification of recommendations as defined by the Canadian Task Force on Preventive Health Care

 

Chemotherapy

“Ovarian reserve” refers to the population of primordial follicles in the ovary; those follicles make up more than 90% of the follicular population at any given time. The ovarian pool of oocytes and their individual reproductive potential decline with age, as reflected in diminishing fecundity rates and pregnancy rates with medical fertility treatments911. Chemotherapeutic agents appear simply to accelerate that process12. The gonadotoxicity of combination chemotherapy treatments varies according to the specific agents used, their cumulative doses, the protocol used, and the reproductive potential of the patient at the time of treatment13,14. Cyclophosphamide and other alkylating agents are the most toxic to the ovary, producing a dose-dependent exponential decline in primordial follicle density15,16. Compared with other regimens, cyclophosphamide-containing protocols are 4 times more likely to result in ovarian failure, with almost 80% of failures occurring within the first year13. Protocols are classified into low, intermediate, or high risk of inducing ovarian failure, with the incidence of menopause ranging from less than 20% to more than 80%17,18.

Quantifying the gonadotoxic effects of each chemotherapeutic regimen is difficult and, to date, poorly studied. Most existing clinical trials and population studies for chemotherapeutic agents report the incidence of premature ovarian failure and ovulatory dysfunction as the measure of fertility. Infertility and diminished ovarian reserve are typically associated with eumenorrhea and ovulatory cycles19. Destruction of pre-ovulatory follicles results in temporary amenorrhea for a period of 3–4 months; however, long-term ovarian function can be maintained by as little as 10% of the ovary, and so clinical measures of menstrual function are a poor benchmark for assessing ovarian damage20. In the absence of long term follow-up of fertility and pregnancy outcomes, the effects of cancer treatment on future reproductive function will be underestimated.

As expected, the incidences of acute ovarian failure, infertility, and early menopause in chemotherapy patients correlates with age19. Regardless of the type of chemotherapy agents administered, at least a fraction of ovarian reserve will be lost, even if that loss is not immediately apparent with clinical and laboratory evaluation. Most objective measures of ovarian reserve are altered by chemotherapy21. Low-risk treatments such as doxorubicin–bleomycin–vinblastine–dacarbazine for Hodgkin lymphoma appear to have minimal short-term effects on reproduction in women under 30 years of age, but clear effects in both menstrual function and ovarian reserve testing are seen in older age groups22. Even if a patient is deemed to be at low risk for premature menopause, a shorter reproductive life can be expected even if regular menstrual cycles resume23,24.

Anecdotal experience suggests that cancer survivors with a history of chemotherapy have poor outcomes with medical fertility treatments. Youth is certainly a protective factor, but long-term follow-up of childhood cancer patients demonstrates clear effects on ovarian reserve and reproductive potential later in life2531. Fortunately, chemotherapeutic agents do not appear to have long-term effects on the genetic competency of surviving oocytes or on the future pregnancies themselves32, but based on murine data, the risk of fetal malformation might be elevated for up to 6–12 months after exposure33. Overall, the most commonly used combination chemotherapies likely advance a woman’s reproductive age by 10 years, with onset of menopause depending on the patient’s ovarian reserve at the start of treatment34.

Radiation Therapy

Like chemotherapy agents, ionizing radiation has an impact on the female reproductive tract that is related to age at exposure and effective dose (fractionation schedule)35,36. Abdominopelvic irradiation can lead to high rates of premature ovarian failure, with even less than 2 Gy causing loss of more than 50% of the primordial follicle pool37,38. By comparison, typical doses for gynecologic malignancies total 50 Gy. Hypothalamic–pituitary–gonadal function can be impaired by cranial irradiation, with the highest incidence of central hypogonadism occurring with doses above 30–40 Gy39,40. Other risk factors for premature ovarian failure include concurrent administration of alkylating agents, high-dose radiation, and the diagnosis of Hodgkin lymphoma38.

Pelvic irradiation impairs fertility and is associated with poor pregnancy outcomes, including early and midtrimester loss, preterm birth, and low birthweight41. The pathophysiology appears to involve vascular, endometrial, and myometrial damage31,42. Exposure before completion of puberty impairs normal uterine development, with a resulting reduced adult uterine volume that is refractory to estrogen replacement therapy. The potential need for gestational surrogacy should be discussed in such cases.

GUIDELINES

Early Access to Care and Barriers to Referral

In 2006, the American Society of Clinical Oncology set out to provide guidance to oncologists about fertility preservation and concluded that the process of informed consent requires a discussion of future fertility issues and options for fertility preservation17. An algorithm was suggested, which includes provision of counselling from a structured group including the medical oncologist, a reproductive endocrinologist, and a psychologist. Ideally, a collaborative multidisciplinary team of this kind would satisfy the need for a patient-centred approach to determining a realistic likelihood of success given all the factors that can play into such a multifaceted issue. Recently, a collaborative group called the Cancer Knowledge Network (http://www.cancerkn.com) was established in Canada. The network endeavors to educate patients and professionals and to connect patients with their regional fertility preservation services.

Despite the American Society of Clinical Oncology recommendation, some cancer specialists do not routinely discuss fertility preservation, and nearly half never refer patients to a fertility specialist43. Many barriers have been identified, including a lack of knowledge about fertility preservation options44 and available local resources45,46, and the perception that assisted reproductive technologies are cost-prohibitive and of limited efficacy47,48. The constraints of time and concern about cancer treatment delay are also cited, but early involvement of the fertility specialist is critical for the provision of timely fertility preservation services49,50. In a direct comparison of patients undergoing fertility preservation treatments with those undergoing standard cancer treatment protocols, no statistical or clinical differences were observed between the groups with respect to time from initial diagnosis to chemotherapy initiation or time from definitive operation to chemotherapy (p ≤ 0.27 and p ≤ 0.79 respectively)51. The median time from referral to oocyte retrieval was 32 days (range: 13–66 days)51, with a multidisciplinary team arranging in vitro fertilization (ivf) within 18 days from referral (median of 11 days for ovarian stimulation)52. Chemotherapy can actually start up to 3 weeks earlier if a fertility preservation referral is made before cancer surgery53. Collaborative efforts between the fertility specialist and the oncology team should aim to provide informed counselling about future infertility and the suitability of individualized fertility preservation treatments54. Such counselling requires early referral and timely consultation with a fertility specialist, with the provision of fertility preservation treatment in conjunction with the oncologic management schedule.

Recommendations

After a diagnosis of cancer or another medical condition requiring potentially sterilizing medical or surgical treatments in a reproductive-age woman, immediate referral to a reproductive endocrinology and infertility specialist is strongly suggested to provide patients with counselling about their fertility and fertility preservation management options (level ii-B).

A multidisciplinary network to facilitate referrals to professionals with expertise in fertility preservation should be considered (level ii-3B).

Assessment of the Young Cancer Patient

Before considering fertility preservation treatments, the patient must consider the individualized risk that the cancer treatment poses to future fertility. In the case of breast cancer, practitioners should be mindful of the 2-year period of observation after completion of chemotherapy and the lengthy delays that the use of adjuvant hormonal therapies implies. It is important that the oncology team be consulted before fertility preservation treatment is initiated. Careful coordination of the fertility preservation treatments might be required to allow for timely delivery of cancer treatment, with a clear understanding having been reached with the patient that cure takes precedence over fertility.

Ovarian reserve testing should be considered to help in developing the ovarian stimulation protocol and to provide a reasonable estimate of age-related prognosis. For many years, basal follicle-stimulating hormone (fsh) has been the standard evaluation of ovarian reserve and a simple means to screen patients for diminished response and poor outcome with ivf55. Antimüllerian hormone (amh) is proving to be the most predictive for ovarian response to exogenous gonadotropins and for pregnancy outcome, and also the most versatile in such patients5658. Antimüllerian hormone is detectable at all ages and, unlike fsh, is stable throughout the menstrual cycle; it can therefore be assessed at the time of presentation. In combination with the patient’s age, amh can help to assess future fertility by quantifying the short-term chemotoxic effects on ovarian reserve59, providing an estimated age of menopause60,61 and assessing the patient’s susceptibility to the gonadotoxic effects of chemotherapy62,63.

Like fsh, amh is a better predictor of oocyte numbers and ovarian response to gonadotropins than it is of successful pregnancy64,65. Complete transvaginal pelvic ultrasonography with antral follicle count is an essential part of basic fertility assessment in prospective patients66. In addition to providing further data about the patient’s ovarian reserve67,68, pre-treatment ultrasonography also evaluates for pelvic pathology and adnexal anatomy in preparation for controlled ovarian stimulation and oocyte harvest.

Recommendations

All or some combination of serum fsh, serum amh, and antral follicle count should be performed before chemotherapy to assist in the selection of gonadotropin doses and to prognosticate the gonadotoxic effects of chemotherapy (level ii-2B).

Follow-up serum fsh and amh should be considered for assessing the gonadotoxic effects of chemotherapy (level ii-2A).

Fertility Preservation Options

On the basis of a fertility assessment, the oncologic treatment plan, and the patient’s reproductive needs, individualized fertility preservation plans can be formulated for most patients. The decision to proceed with fertility preservation treatments should take into account age, diagnosis, oncology treatment regimen, reproductive potential with and without treatment, and the patient’s personal or social situation. More universally, gonadotropin-releasing hormone (gnrh) agonists administered concurrently with cytotoxic treatments in an effort to provide some level of protection are suitable for all ages. Assisted reproductive technologies have been used to generate oocytes and embryos for cryopreservation and future use. Creation of embryos requires sperm from a partner (or when there is no partner, donor sperm). Oocyte vitrification is proving to be an excellent option for women even when a partner is present because it provides the patient with reproductive autonomy. In vitro maturation is an investigational strategy available through a limited number of centres. Although also investigational, ovarian tissue cryopreservation is the most hopeful option for children and young adolescents who are otherwise limited by their reproductive immaturity.

GnRH Agonists

Reports of reduced amenorrhea rates in young women using adjuvant gnrh agonists prompted investigation of the chemoprotective properties of those agents in the ovary. Despite limited evidence for their efficacy, gnrh agonists are currently in routine use at some centres during chemotherapy. Proposed mechanisms of action include hypogonadotropism-induced ovarian quiescence, reduction of ovarian blood flow, and agonistic effects on ovarian gnrh receptors. Three small prospective randomized studies have assessed gnrh agonists, with two studies demonstrating a reduction in premature ovarian failure, one of which reported a reduction to 11.4% from 66.6%6971. A meta-analysis also showed a protective effect; however, most studies used historical controls72.

A potential concern with the use of gnrh agonists in breast cancer patients is that the resulting hypoestrogenic state could inadvertently arrest malignant cells in the resting (G0) phase, rendering them less susceptible to chemotherapy73,74. Larger studies are required to better evaluate the efficacy of gnrh agonists.

Recommendation:

Before combination chemotherapy, gnrh agonists can be considered as a means of gonadal cytoprotection (level i-B).

Embryo Cryopreservation

Cryopreservation of embryos is a standard technique used by all ivf clinics for the banking of supernumerary embryos and for situations in which the transfer of fresh embryos is ill-advised, such as in severe cases of ovarian hyperstimulation syndrome (ohss)75. As a method of fertility preservation, embryo cryopreservation has been available to cancer patients for many years. Foremost with this technique is the need for a male partner, unless the patient is prepared to use donor sperm. The patient’s chance of a successful future pregnancy depends on the number of high-quality embryos obtained, which in turn depends on the number of ivf cycles and the time available to achieve adequate stimulation. In 2012, the clinical pregnancy rate for frozen embryo transfer by the 32 ivf facilities in Canada was 29.9%76. With all of the necessary resources at hand, many ivf facilities routinely cryopreserve embryos as a means of fertility preservation in patients with male partners or in those who wish to use donor sperm.

Recommendation:

Embryo cryopreservation is a recommended method of fertility preservation (level i-A).

Oocyte Cryopreservation

For women without a male partner or women desiring reproductive autonomy, oocyte cryopreservation has become the standard approach. Historically, the technique has been beset by lower pregnancy rates than those associated with embryo cryopreservation; however, with recent advances in cryo-technology, the service is becoming more widely available77. The low pregnancy rates were related to several technical challenges encountered during the freeze–thaw process and the in vitro maturation of immature oocytes.

Mature oocytes provide the best chance for pregnancy, but have several characteristics that make them susceptible to cryo-damage. The oocyte’s large size (low ratio of surface area to volume) and high water content make it vulnerable to ice crystal formation, rupture, and limited penetration of cryoprotectant solutions78. Because mature oocytes are arrested in metaphase ii, the spindle apparatus is fully extended and prone to disassembly at lower temperature, with subsequent chromosome dispersion and aneuploidy79,80. Despite the potential obstacles, clinical and neonatal outcomes to date attest to the safety of this technology81. The efficiency, feasibility, and safety of the technology have developed to the point that the American Society for Reproductive Medicine no long considers it experimental for the purpose of fertility preservation in women undergoing gonadotoxic therapies82,83.

Vitrification has been integral to the improvements in and success of oocyte cryopreservation. The technique directly solidifies the oocyte and surrounding solution into a glasslike (vitreous) state, minimizing the formation of potentially disruptive intracellular and extracellular ice crystals. Meta-analyses support the superior thawing survival and clinical outcomes achieved with oocyte vitrification8486. A recent randomized controlled trial demonstrated the clinical equivalency of vitrified and fresh oocytes in the setting of anonymous oocyte donation87. Other groups are also starting to report similar success, and the technique has quickly become the standard approach for both oocyte and embryo cryopreservation88. With refinements in technique and better clinical outcomes, oocyte cryopreservation is proving to be a simple and versatile method of fertility preservation that can provide women with reproductive autonomy.

Recommendation:

Oocyte cryopreservation by vitrification is a recommended method of fertility preservation (level i-A).

Controlled Ovarian Stimulation in Cancer Patients

Using modern ivf protocols and appropriate doses of gonadotropins, oocyte and embryo yield and, ultimately, the number of future attempts for pregnancy can be maximized. In the case of breast cancer, a period of 4–6 weeks between surgery and chemotherapy is a common restriction, allowing for only 1 or 2 ivf cycle attempts, given that gonadotropins are traditionally initiated with menses.

Protocols using gnrh antagonists provide the most flexibility during ovarian stimulation. Treatments with gnrh antagonists are shorter, require less gonadotropin, and reduce the risk of ohss8992. Gonadotropins can be initiated with spontaneous menses, by truncation of the menstrual cycle with the administration of a gnrh antagonist shortly after ovulation93, or randomly throughout the patient’s cycle9498.

The dose of gonadotropins should be individualized to the patient based on age and ovarian reserve testing, with the goals of maximizing the number of high-grade embryos at the end of the process and of not compromising the patient’s medical status before the start of cancer treatments. Data to suggest that these patients have different gonadotropin requirements or that the quality of the oocytes and embryos are compromised by their illness are minimal, but dosing decisions should be left to a physician with experience using gonadotropins in these patients99. In an attempt to minimize the patient’s estrogen exposure after oocyte retrieval and her risk of early ohss, gnrh agonists can be used with antagonist cycles for triggering final oocyte maturation100102. Like oocyte donors, these patients are not at risk for the more clinically worrisome late ohss because they are not conceiving. Given that inadequate induction of the luteinizing hormone surge is the principal risk of the technique, reserving the gnrh agonist “trigger” for patients with a hyper-response or supplementing with a small dose of human chorionic gonadotropin is also acceptable101,103,104. In such cases, gnrh antagonist protocols are preferred for several reasons, but are often the most practical option given that gonadotropins can be started quickly.

Long gnrh agonist protocols are still used for controlled ovarian stimulation, but have the well-recognized risk of inducing a luteal “flare” from the pituitary, with rescue of the corpus luteum and functional ovarian cysts leading to treatment delays105.

Recommendations:

Ovarian stimulation protocols using gnrh antagonists should be considered for embryo and oocyte cryopreservation (level ii-3B).

To minimize the risk of ohss, gnrh agonists are recommended for the induction of oocyte maturation when using gnrh antagonist cycles (level i-2A).

Use of Cytoprotective Agents During Ovarian Stimulation in Breast Cancer Patients

Many breast cancer tumour cells are estrogen receptor–positive and accordingly are susceptible to environments with estrogen excess106,107. Even tumours that are classified as receptor-negative will contain a small percentage of receptor-positive cells92,108,109.

Serum estradiol levels reach supraphysiologic levels during controlled ovarian stimulation: typically 5000 pmol/mL and not uncommonly exceeding 10,000 pmol/mL (peak natural cycle levels are 750–1300 pmol/mL). Although no clinical data are currently available, high levels of estrogens could in theory stimulate subclinical disseminated disease110, and so any therapy that antagonizes the effect is reasonable111113. Two strategies are commonly used to minimize that estrogen exposure: recovering oocytes from an unstimulated ivf cycle, or administering cytoprotective agents in combination with gonadotropin stimulation.

Aromatase inhibitors have proved to be efficacious as an adjuvant therapy for the management of micrometastatic disease111,114116, and they have gained popularity as ovulation induction agents and adjuncts in ivf protocols117. More importantly for the breast cancer patient, they suppress estradiol production during ivf stimulation. Letrozole is the most potent of the aromatase inhibitors, suppressing greater than 96% of estradiol activity. With concurrent use of aromatase inhibitors, gonadotropins can be administered to maximize embryo yield while minimizing estradiol levels118,119. Ultrasound follicle tracking serves as the only measure for dosing adjustment and assessing the patient’s risk for ohss. Because the ovary remains hyperstimulated well beyond retrieval of the oocytes, sustained use of letrozole for at least another 7 days is recommended.

Recommendation:

In women with breast cancer and other estrogen-sensitive diseases, aromatase inhibitors should be considered when administering gonadotropins (level ii-3B).

Ovarian Cryopreservation and Transplantation

Any patient receiving chemotherapy or radiotherapy that targets the ovarian follicles can be considered a candidate for ovarian cryopreservation, assuming a low risk for ovarian metastasis120. Also, some patients might not have sufficient time to undergo ovarian stimulation for oocyte or embryo freezing, or might have an oncology plan that includes abdominal surgery.

Since the first experiments with ovarian transplantation in animals121, steady advances have been made in humans, and other species have also been successfully transplanted with both autologous ovarian tissue and human xenografts122. With the knowledge gained from those experiments, trials in human transplantation were initiated. In the case of cancer patients, caution should be exercised to prevent the reintroduction of disease. Transmission of cancer has been demonstrated in the animal model123,124, and metastatic seeding of the ovary commonly occurs with some cancers. In the case of BRCA mutation, the risk of ovarian cancer is significant; screening for the mutation should therefore be considered in all breast cancer patients before ovarian tissue harvest125.

At an appropriate time after completion of the patient’s cancer therapy, the tissue is thawed and transplanted either orthotopically or heterotopically within subcutaneous tissue or the pelvis126130. The major barrier to the technology is delayed revascularization and the resulting ischemia and fibrosis, with subsequent loss of primordial follicles121,131. Grafts become hormonally active 3–4 months after transplantation, at which time oocyte harvesting can be attempted, with or without the aid of exogenous gonadotropins to stimulate follicle development. To date, more than 23 live births have been reported in humans; however, some could have originated from the contralateral in situ ovary, because only one ovary is typically harvested132138. Several groups are currently experimenting with whole-ovary vitrification and transplantation as a means to improve efficiency and clinical outcomes139142. Given the limited success of that technology to date, the potential for reseeding of metastatic disease, and the surgical risks, ovarian transplantation should still be considered investigational and limited to cases in which oophorectomy is planned. The procedure is further constrained by the limited number of individuals and facilities with expertise in the technique.

Recommendation:

Ovarian tissue cryopreservation and transplantation is investigational and should be limited to cases of oophorectomy or other predetermined abdominal surgeries by surgeons with the necessary experience, and in connection with clinical research approved by a research ethics board (level ii-3B).

Pregnancy After Cancer

No consensus has emerged about the best time to conceive after cancer treatments. Because most recurrences are diagnosed within the first 2 years, patients are commonly asked by their oncologists to wait. However, some studies suggest that early conception does not negatively affect survival143,144. Five-year survival is actually higher in breast cancer patients who achieve a pregnancy145,146, although that observation could certainly be related to a “healthy patient” bias. Ultimately, decisions about the timing of pregnancy should be made in consultation with a cancer specialist.

Fertility-Sparing Surgical Options

The harmful effects of radiation on the ovaries can be minimized by ovarian transposition, a procedure in which the ovaries are surgically transposed to a location outside the radiation field147. Transposition can also be combined with gonadal shielding to further reduce the dose effect148. Using transposition, preservation of menstrual function have been reported to range from 65% to more than 88%149151. The risks associated with the procedure include ovarian cysts, adhesions, pelvic pain, ovarian migration, premature ovarian failure, and tubal injury20,152. Some malignancies carry a small risk of metastatic disease to the ovary, and so transposition could facilitate the spread of disease20,153,154. Any benefit of transposition can be lost when adjuvant chemotherapy is used155,156. Other fertility-sparing surgical options include cervical conization or trachelectomy for select early-stage cervical cancer patients, and unilateral oophorectomy or cystectomy in select ovarian neoplasms157,158.

Recommendation:

When possible, fertility-sparing surgery should be considered if it does not compromise survival (level iii-B).

Ethics Considerations

Standard treatments confer an overall net benefit to the patient, but when the treatments are experimental, the benefit must be carefully considered. The evolving field of oncofertility uses investigational procedures with the aim of improving outcomes. For such interventions, the guidance of an institutional review board is recommended, with formal protocols and associated consent forms clearly stating the proposed treatment as investigational.

The consent process for women of all ages should include a discussion of these topics:

  • □ Risk to future fertility of cancer treatments

  • □ Fertility preservation treatment options

  • □ Risks of delaying cancer treatment

  • □ Any investigational aspects of fertility preservation treatments

  • □ Realistic likelihood of the success of fertility preservation options

  • □ Potential risks of fertility preservation treatments

  • □ Treatment costs

  • □ Disposition of human reproductive material

  • □ Posthumous reproduction

  • □ Alternative fertility options (oocyte donation, adoption, gestational surrogacy)

SUMMARY

Recent strides in the technology of oocyte and embryo cryopreservation provide effective fertility preservation options through assisted reproductive technologies in Canada. A multidisciplinary approach and education of oncology professionals will help to ensure that cancer patients receive the appropriate fertility preservation counselling and services.

ACKNOWLEDGMENTS

The authors thank the Canadian Fertility and Andrology Society clinical practice guideline committee.

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare that we have none.

REFERENCES

1. Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2013. Toronto, ON: Canadian Cancer Society; 2013.

2. Aebi S, Gelber S, Castiglione-Gertsch M, et al. Is chemotherapy alone adequate for young women with oestrogen-receptor-positive breast cancer? Lancet 2000;355:1869–74.
cross-ref  pubmed  

3. Bentzon N, During M, Rasmussen BB, Mouridsen H, Kroman N. Prognostic effect of estrogen receptor status across age in primary breast cancer. Int J Cancer 2008;122:1089–94.
cross-ref  

4. Adami HO, Malker B, Holmberg L, Persson I, Stone B. The relation between survival and age at diagnosis in breast cancer. N Engl J Med 1986;315:559–63.
cross-ref  pubmed  

5. Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor–positive breast cancer. J Clin Oncol 2010;28:3784–96.
cross-ref  pubmed  

6. Jemal A, Thun MJ, Ries LA, et al. Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 2008;100:1672–94.
cross-ref  pubmed  pmc  

7. Canadian Task Force on the Periodic Health Examination. The Canadian Guide to Clinical Preventive Health Care. Ottawa, ON: Canada Communications Group; 1994: p. xxxvii.

8. Canadian Task Force on Preventive Health Care. New grades for recommendations from the Canadian Task Force on Preventive Health Care. CMAJ 2003;169:207–8.
pubmed  pmc  

9. Gunby J, Bissonnette F, Librach C, Cowan L on behalf of the ivf Directors Group of the Canadian Fertility and Andrology Society. Assisted reproductive technologies (art) in Canada: 2007 results from the Canadian art Register. Fertil Steril 2011;95:542–7.e1–10.
cross-ref  

10. Tietze C. Reproductive span and rate of reproduction among Hutterite women. Fertil Steril 1957;8:89–97.
pubmed  

11. van Noord-Zaadstra BM, Looman CW, Alsbach H, Habbema JD, te Velde ER, Karbaat J. Delaying childbearing: effect of age on fecundity and outcome of pregnancy. BMJ 1991;302:1361–5.
cross-ref  pubmed  pmc  

12. Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PloS One 2010;5:e8772.
cross-ref  pubmed  pmc  

13. Goodwin PJ, Ennis M, Pritchard KI, Trudeau M, Hood N. Risk of menopause during the first year after breast cancer diagnosis. J Clin Oncol 1999;17:2365–70.
pubmed  

14. Arnon J, Meirow D, Lewis-Roness H, Ornoy A. Genetic and teratogenic effects of cancer treatments on gametes and embryos. Hum Reprod Update 2001;7:394–403.
cross-ref  pubmed  

15. Meirow D, Lewis H, Nugent D, Epstein M. Subclinical depletion of primordial follicular reserve in mice treated with cyclophosphamide: clinical importance and proposed accurate investigative tool. Hum Reprod 1999;14:1903–7.
cross-ref  pubmed  

16. Walshe JM, Denduluri N, Swain SM. Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer. J Clin Oncol 2006;24:5769–79.
cross-ref  pubmed  

17. Lee SJ, Schover LR, Partridge AH, et al. on behalf of the American Society of Clinical Oncology. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol 2006;24:2917–31.
cross-ref  pubmed  

18. Hickey M, Peate M, Saunders CM, Friedlander M. Breast cancer in young women and its impact on reproductive function. Hum Reprod Update 2009;15:323–39.
cross-ref  pubmed  pmc  

19. 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;118:1933–9.
cross-ref  

20. Wo JY, Viswanathan AN. Impact of radiotherapy on fertility, pregnancy, and neonatal outcomes in female cancer patients. Int J Radiat Oncol Biol Phys 2009;73:1304–12.
cross-ref  pubmed  pmc  

21. Anderson RA, Themmen AP, Al-Qahtani A, Groome NP, Cameron DA. The effects of chemotherapy and long-term gonadotrophin suppression on the ovarian reserve in premenopausal women with breast cancer. Hum Reprod 2006;21:2583–92.
cross-ref  pubmed  

22. Behringer K, Mueller H, Goergen H, et al. Gonadal function and fertility in survivors after Hodgkin lymphoma treatment within the German Hodgkin Study Group HD13 to HD15 trials. J Clin Oncol 2013;31:231–9.
cross-ref  

23. Partridge A, Gelber S, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Winer E. Age of menopause among women who remain premenopausal following treatment for early breast cancer: long-term results from International Breast Cancer Study Group Trials v and vi. Eur J Cancer 2007;43:1646–53.
cross-ref  pubmed  

24. Sklar C. Maintenance of ovarian function and risk of premature menopause related to cancer treatment. J Natl Cancer Inst Monogr 2005;:25–7.
cross-ref  pubmed  

25. Larsen EC, Muller J, Schmiegelow K, Rechnitzer C, Andersen AN. Reduced ovarian function in long-term survivors of radiation- and chemotherapy-treated childhood cancer. J Clin Endocrinol Metab 2003;88:5307–14.
cross-ref  pubmed  

26. Larsen EC, Muller J, Rechnitzer C, Schmiegelow K, Andersen AN. Diminished ovarian reserve in female childhood cancer survivors with regular menstrual cycles and basal fsh <10 IU/L. Hum Reprod 2003;18:417–22.
cross-ref  pubmed  

27. Bath LE, Wallace WH, Shaw MP, Fitzpatrick C, Anderson RA. Depletion of ovarian reserve in young women after treatment for cancer in childhood: detection by anti-mullerian hormone, inhibin B and ovarian ultrasound. Hum Reprod 2003;18:2368–74.
cross-ref  pubmed  

28. Johnston RJ, Wallace WH. Normal ovarian function and assessment of ovarian reserve in the survivor of childhood cancer. Pediatr Blood Cancer 2009;53:296–302.
cross-ref  pubmed  

29. Thomas-Teinturier C, El Fayech C, Oberlin O, et al. Age at menopause and its influencing factors in a cohort of survivors of childhood cancer: earlier but rarely premature. Hum Reprod 2013;28:488–95.
cross-ref  

30. Barton SE, Najita JS, Ginsburg ES, et al. Infertility, infertility treatment, and achievement of pregnancy in female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study cohort. Lancet Oncol 2013;14:873–81.
cross-ref  pubmed  pmc  

31. Reulen RC, Zeegers MP, Wallace WH, et al. on behalf of the British Childhood Cancer Survivor Study. Pregnancy outcomes among adult survivors of childhood cancer in the British Childhood Cancer Survivor Study. Cancer Epidemiol Biomarkers Prev 2009;18:2239–47.
cross-ref  pubmed  pmc  

32. Edgar AB, Wallace WH. Pregnancy in women who had cancer in childhood. Eur J Cancer 2007;43:1890–4.
cross-ref  pubmed  

33. Meirow D, Epstein M, Lewis H, Nugent D, Gosden RG. Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations. Hum Reprod 2001;16:632–7.
cross-ref  pubmed  

34. Duffy CM, Allen SM, Clark MA. Discussions regarding reproductive health for young women with breast cancer undergoing chemotherapy. J Clin Oncol 2005;23:766–73.
cross-ref  pubmed  

35. Meirow D, Biederman H, Anderson RA, Wallace WH. Toxicity of chemotherapy and radiation on female reproduction. Clin Obstet Gynecol 2010;53:727–39.
cross-ref  pubmed  

36. Ash P. The influence of radiation on fertility in man. Br J Radiol 1980;53:271–8.
cross-ref  pubmed  

37. Wallace WH, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte. Hum Reprod 2003;18:117–21.
cross-ref  pubmed  

38. Sklar CA, Mertens AC, Mitby P, et al. Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 2006;98:890–6.
cross-ref  pubmed  

39. 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;27:2374–81.
cross-ref  pubmed  pmc  

40. Green DM, Nolan VG, Kawashima T, et al. Decreased fertility among female childhood cancer survivors who received 22–27 Gy hypothalamic/pituitary irradiation: a report from the Childhood Cancer Survivor Study. Fertil Steril 2011;95:1922–7,1927.e1.
cross-ref  

41. Critchley HO, Wallace WH. Impact of cancer treatment on uterine function. J Natl Cancer Inst Monogr 2005;:64–8.
cross-ref  pubmed  

42. Signorello LB, Cohen SS, Bosetti C, et al. Female survivors of childhood cancer: preterm birth and low birth weight among their children. J Natl Cancer Inst 2006;98:1453–61.
cross-ref  pubmed  pmc  

43. Forman EJ, Anders CK, Behera MA. Pilot survey of oncologists regarding treatment-related infertility and fertility preservation in female cancer patients. J Reprod Med 2009;54:203–7.
pubmed  pmc  

44. Blumenfeld Z, Avivi I, Ritter M, Rowe JM. Preservation of fertility and ovarian function and minimizing chemotherapy-induced gonadotoxicity in young women. J Soc Gynecol Investig 1999;6:229–39.
cross-ref  pubmed  

45. Goodwin T, Oosterhuis BE, Kiernan M, Hudson MM, Dahl GV. Attitudes and practices of pediatric oncology providers regarding fertility issues. Pediatr Blood Cancer 2007;48:80–5.
cross-ref  

46. Quinn GP, Vadaparampil ST, Gwede CK, et al. Discussion of fertility preservation with newly diagnosed patients: oncologists’ views. J Cancer Surviv 2007;1:146–55.
cross-ref  

47. Woodruff TK. The Oncofertility Consortium—addressing fertility in young people with cancer. Nat Rev Clin Oncol 2010;7:466–75.
cross-ref  pubmed  pmc  

48. Quinn GP, Vadaparampil ST, Bell-Ellison BA, Gwede CK, Albrecht TL. Patient–physician communication barriers regarding fertility preservation among newly diagnosed cancer patients. Soc Sci Med 2008;66:784–9.
cross-ref  

49. Vadaparampil S, Quinn G, King L, Wilson C, Nieder M. Barriers to fertility preservation among pediatric oncologists. Patient Educ Couns 2008;72:402–10.
cross-ref  pubmed  

50. Schover LR, Brey K, Lichtin A, Lipshultz LI, Jeha S. Oncologists’ attitudes and practices regarding banking sperm before cancer treatment. J Clin Oncol 2002;20:1890–7.
cross-ref  pubmed  

51. Baynosa J, Westphal LM, Madrigrano A, Wapnir I. Timing of breast cancer treatments with oocyte retrieval and embryo cryopreservation. J Am Coll Surg 2009;209:603–7.
cross-ref  pubmed  

52. Jenninga E, Louwe LA, Peters AA, Nortier JW, Hilders CG. Timing of fertility preservation procedures in a cohort of female patients with cancer. Eur J Obstet Gynecol Reprod Biol 2012;160:170–3.
cross-ref  

53. Lee 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;28:4683–6.
cross-ref  pubmed  pmc  

54. Noyes N, Knopman JM, Melzer K, Fino ME, Friedman B, Westphal LM. Oocyte cryopreservation as a fertility preservation measure for cancer patients. Reprod Biomed Online 2011;23:323–33.
cross-ref  pubmed  

55. Scott RT Jr, Elkind-Hirsch KE, Styne-Gross A, Miller KA, Frattarelli JL. The predictive value for in vitro fertility delivery rates is greatly impacted by the method used to select the threshold between normal and elevated basal follicle-stimulating hormone. Fertil Steril 2008;89:868–78.
cross-ref  

56. Riggs RM, Duran EH, Baker MW, et al. Assessment of ovarian reserve with anti-mullerian hormone: a comparison of the predictive value of anti-mullerian hormone, follicle-stimulating hormone, inhibin B, and age. Am J Obstet Gynecol 2008;199:202.e1–8.
cross-ref  

57. Arce JC, La Marca A, Mirner Klein B, Nyboe Andersen A, Fleming R. Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles: prediction of ovarian response and cumulative treatment outcome in good-prognosis patients. Fertil Steril 2013;99:1644–53.
cross-ref  pubmed  

58. Brodin T, Hadziosmanovic N, Berglund L, Olovsson M, Holte J. Antimüllerian hormone levels are strongly associated with live-birth rates after assisted reproduction. J Clin Endocrinol Metab 2013;98:1107–14.
cross-ref  pubmed  

59. Brougham MF, Crofton PM, Johnson EJ, Evans N, Anderson RA, Wallace WH. Anti-mullerian hormone is a marker of gonadotoxicity in pre- and postpubertal girls treated for cancer: a prospective study. J Clin Endocrinol Metab 2012;97:2059–67.
cross-ref  pubmed  

60. de Vet A, Laven JS, de Jong FH, Themmen AP, Fauser BC. Antimüllerian hormone serum levels: a putative marker for ovarian aging. Fertil Steril 2002;77:357–62.
cross-ref  pubmed  

61. Freeman EW, Sammel MD, Lin H, Gracia CR. Anti-mullerian hormone as a predictor of time to menopause in late reproductive age women. J Clin Endocrinol Metab 2012;97:1673–80.
cross-ref  pubmed  pmc  

62. Anders C, Marcom PK, Peterson B, et al. A pilot study of predictive markers of chemotherapy-related amenorrhea among premenopausal women with early stage breast cancer. Cancer Invest 2008;26:286–95.
cross-ref  pubmed  pmc  

63. Anderson RA, Cameron DA. Pretreatment serum anti-müllerian hormone predicts long-term ovarian function and bone mass after chemotherapy for early breast cancer. J Clin Endocrinol Metab 2011;96:1336–43.
cross-ref  pubmed  

64. Hamre H, Kiserud CE, Ruud E, Thorsby PM, Fossa SD. Gonadal function and parenthood 20 years after treatment for childhood lymphoma: a cross-sectional study. Pediatr Blood Cancer 2012;59:271–7.
cross-ref  

65. Hagen CP, Vestergaard S, Juul A, et al. Low concentration of circulating antimüllerian hormone is not predictive of reduced fecundability in young healthy women: a prospective cohort study. Fertil Steril 2012;98:1602–8.e2.
cross-ref  

66. Chang MY, Chiang CH, Hsieh TT, Soong YK, Hsu KH. Use of the antral follicle count to predict the outcome of assisted reproductive technologies. Fertil Steril 1998;69:505–10.
cross-ref  pubmed  

67. Wallace WH, Kelsey TW. Ovarian reserve and reproductive age may be determined from measurement of ovarian volume by transvaginal sonography. Hum Reprod 2004;19:1612–17.
cross-ref  pubmed  

68. Scheffer GJ, Broekmans FJ, Looman CW, et al. The number of antral follicles in normal women with proven fertility is the best reflection of reproductive age. Hum Reprod 2003;18:700–6.
cross-ref  pubmed  

69. Waxman JH, Ahmed R, Smith D, et al. Failure to preserve fertility in patients with Hodgkin’s disease. Cancer Chemother Pharmacol 1987;19:159–62.
cross-ref  

70. Badawy A, Elnashar A, El-Ashry M, Shahat M. Gonadotropin-releasing hormone agonists for prevention of chemotherapy-induced ovarian damage: prospective randomized study. Fertil Steril 2009;91:694–7.
cross-ref  

71. Giuseppe L, Attilio G, Edoardo DN, Loredana G, Cristina L, Vincenzo L. Ovarian function after cancer treatment in young women affected by Hodgkin disease (hd). Hematology 2007;12:141–7.
cross-ref  pubmed  

72. Clowse ME, Behera MA, Anders CK, et al. Ovarian preservation by gnrh agonists during chemotherapy: a meta-analysis. J Womens Health (Larchmt) 2009;18:311–19.
cross-ref  

73. Emons G, Grundker C, Gunthert AR, Westphalen S, Kavanagh J, Verschraegen C. gnrh antagonists in the treatment of gynecological and breast cancers. Endocr Relat Cancer 2003;10:291–9.
cross-ref  pubmed  

74. Mullen P, Scott WN, Miller WR. Growth inhibition observed following administration of an lhrh agonist to a clonal variant of the MCF-7 breast cancer cell line is accompanied by an accumulation of cells in the G0/G1 phase of the cell cycle. Br J Cancer 1991;63:930–2.
cross-ref  pubmed  pmc  

75. D’Angelo A, Amso N. Embryo freezing for preventing ovarian hyperstimulation syndrome. Cochrane Database Syst Rev 2002;:CD002806.

76. Gunby J. Assisted Reproductive Technologies (ART) in Canada: 2012 Results from the Canadian ART Register. Montreal, QC: Canadian Fertility and Andrology Society; 2014. [Available at: http://www.cfas.ca/images/stories/pdf/CARTR_2012.pdf; cited 26 June 2015]

77. Rudick B, Opper N, Paulson R, Bendikson K, Chung K. The status of oocyte cryopreservation in the United States. Fertil Steril 2010;94:2642–6.
cross-ref  pubmed  

78. Jain JK, Paulson RJ. Oocyte cryopreservation. Fertil Steril 2006;86(suppl):1037–46.
cross-ref  pubmed  

79. Boiso I, Marti M, Santalo J, Ponsa M, Barri PN, Veiga A. A confocal microscopy analysis of the spindle and chromosome configurations of human oocytes cryopreserved at the germinal vesicle and metaphase ii stage. Hum Reprod 2002;17:1885–91.
cross-ref  pubmed  

80. Cobo A, Rubio C, Gerli S, Ruiz A, Pellicer A, Remohi J. Use of fluorescence in situ hybridization to assess the chromosomal status of embryos obtained from cryopreserved oocytes. Fertil Steril 2001;75:354–60.
cross-ref  pubmed  

81. Noyes N, Porcu E, Borini A. Over 900 oocyte cryopreservation babies born with no apparent increase in congenital anomalies. Reprod Biomed Online 2009;18:769–76.
cross-ref  pubmed  

82. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Mature oocyte cryopreservation: a guideline. Fertil Steril 2013;99:37–43.
cross-ref  

83. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Ovarian tissue and oocyte cryopreservation. Fertil Steril 2006;86(suppl 1):S142–7.
cross-ref  pubmed  

84. Kolibianakis EM, Venetis CA, Tarlatzis BC. Cryopreservation of human embryos by vitrification or slow freezing: which one is better? Curr Opin Obstet Gynecol 2009;21:270–4.
cross-ref  pubmed  

85. Cobo A, Diaz C. Clinical application of oocyte vitrification: a systematic review and meta-analysis of randomized controlled trials. Fertil Steril 2011;96:277–85.
cross-ref  pubmed  

86. Smith GD, Serafini PC, Fioravanti J, et al. Prospective randomized comparison of human oocyte cryopreservation with slow-rate freezing or vitrification. Fertil Steril 2010;94:2088–95.
cross-ref  pubmed  

87. 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;25:2239–46.
cross-ref  pubmed  

88. Nagy ZP, Chang CC, Shapiro DB, et al. Clinical evaluation of the efficiency of an oocyte donation program using egg cryo-banking. Fertil Steril 2009;92:520–6.
cross-ref  

89. Al-Inany HG, Youssef MA, Aboulghar M, et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev 2011;:CD001750.

90. Depalo R, Jayakrishan K, Garruti G, et al. gnrh agonist versus gnrh antagonist in in vitro fertilization and embryo transfer (ivf/et). Reprod Biol Endocrinol 2012;10:26.
cross-ref  

91. Fatemi HM, Blockeel C, Devroey P. Ovarian stimulation: today and tomorrow. Curr Pharm Biotechnol 2012;13:392–7.
cross-ref  

92. Pu D, Wu J, Liu J. Comparisons of gnrh antagonist versus gnrh agonist protocol in poor ovarian responders undergoing ivf. Hum Reprod 2011;26:2742–9.
cross-ref  pubmed  

93. von Wolff M, Thaler CJ, Frambach T, et al. Ovarian stimulation to cryopreserve fertilized oocytes in cancer patients can be started in the luteal phase. Fertil Steril 2009;92:1360–5.
cross-ref  

94. Cakmak H, Katz A, Cedars MI, Rosen MP. Effective method for emergency fertility preservation: random-start controlled ovarian stimulation. Fertil Steril 2013;100:1673–80.
cross-ref  pubmed  

95. Nayak SR, Wakim AN. Random-start gonadotropin-releasing hormone (gnrh) antagonist-treated cycles with gnrh agonist trigger for fertility preservation. Fertil Steril 2011;96:e51–4.
cross-ref  pubmed  

96. Sonmezer M, Turkcuoglu I, Coskun U, Oktay K. Random-start controlled ovarian hyperstimulation for emergency fertility preservation in letrozole cycles. Fertil Steril 2011;95:2125.e9–11.
cross-ref  

97. Buendgen NK, Schultze-Mosgau A, Cordes T, Diedrich K, Griesinger G. Initiation of ovarian stimulation independent of the menstrual cycle: a case–control study. Arch Gynecol Obstet 2013;288:901–4.
cross-ref  pubmed  

98. Bedoschi GM, de Albuquerque FO, Ferriani RA, Navarro PA. Ovarian stimulation during the luteal phase for fertility preservation of cancer patients: case reports and review of the literature. J Assist Reprod Genet 2010;27:491–4.
cross-ref  pubmed  pmc  

99. Cakmak H, Rosen MP. Ovarian stimulation in cancer patients. Fertil Steril 2013;99:1476–84.
cross-ref  pubmed  

100. Oktay K, Turkcuoglu I, Rodriguez-Wallberg KA. gnrh agonist trigger for women with breast cancer undergoing fertility preservation by aromatase inhibitor/fsh stimulation. Reprod Biomed Online 2010;20:783–8.
cross-ref  pubmed  pmc  

101. Humaidan P, Papanikolaou EG, Tarlatzis BC. gnrha to trigger final oocyte maturation: a time to reconsider. Hum Reprod 2009;24:2389–94.
cross-ref  pubmed  

102. Cavagna M, Dzik A. Depot gnrh-agonist trigger for breast-cancer patient undergoing ovarian stimulation resulted in mature oocytes for cryopreservation: a case report. Reprod Biomed Online 2011;22:317–19.
cross-ref  pubmed  

103. Humaidan P, Thomsen LH, Alsbjerg B. gnrha trigger and modified luteal support with one bolus of hcg should be used with caution in extreme responder patients. Hum Reprod 2013;28:2593–4.
cross-ref  pubmed  

104. Humaidan P, Polyzos NP, Alsbjerg B, et al. gnrha trigger and individualized luteal phase hcg support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in ivf patients. Hum Reprod 2013;28:2511–21.
cross-ref  pubmed  

105. Ortmann O, Weiss JM, Diedrich K. Gonadotrophin-releasing hormone (gnrh) and gnrh agonists: mechanisms of action. Reprod Biomed Online 2002;(suppl 1):1–7.
cross-ref  

106. Prest SJ, May FE, Westley BR. The estrogen-regulated protein, tff1, stimulates migration of human breast cancer cells. FASEB J 2002;16:592–4.
pubmed  

107. Allred CD, Ju YH, Allred KF, Chang J, Helferich WG. Dietary genistin stimulates growth of estrogen-dependent breast cancer tumors similar to that observed with genistein. Carcinogenesis 2001;22:1667–73.
cross-ref  pubmed  

108. Babayan A, Hannemann J, Spotter J, Muller V, Pantel K, Joosse SA. Heterogeneity of estrogen receptor expression in circulating tumor cells from metastatic breast cancer patients. PLoS One 2013;8:e75038.
cross-ref  pubmed  pmc  

109. Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN. Overview of resistance to systemic therapy in patients with breast cancer. Adv Exp Med Biol 2007;608:1–22.
cross-ref  pubmed  

110. Henderson IC, Garber JE, Breitmeyer JB, Hayes DF, Harris JR. Comprehensive management of disseminated breast cancer. Cancer 1990;66(suppl):1439–48.
cross-ref  pubmed  

111. Miller WR. Aromatase and the breast: regulation and clinical aspects. Maturitas 2006;54:335–41.
cross-ref  pubmed  

112. Love RR, Van Dinh N, Quy TT, et al. Survival after adjuvant oophorectomy and tamoxifen in operable breast cancer in premenopausal women. J Clin Oncol 2008;26:253–7.
cross-ref  

113. Howell A, Sims AH, Ong KR, Harvie MN, Evans DG, Clarke RB. Mechanisms of disease: prediction and prevention of breast cancer—cellular and molecular interactions. Nat Clin Pract Oncol 2005;2:635–46.
cross-ref  pubmed  

114. Fisher B, Costantino J, Redmond C, et al. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 1989;320:479–84.
cross-ref  pubmed  

115. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003;349:1793–802.
cross-ref  pubmed  

116. Howell A, Locker GY. Defining the roles of aromatase inhibitors in the adjuvant treatment of early-stage breast cancer. Clin Breast Cancer 2005;6:302–9.
cross-ref  pubmed  

117. Schoolcraft WB, Surrey ES, Minjarez DA, Stevens JM, Gardner DK. Management of poor responders: can outcomes be improved with a novel gonadotropin-releasing hormone antagonist/letrozole protocol? Fertil Steril 2008;89:151–6.
cross-ref  

118. Oktay K, Buyuk E, Davis O, Yermakova I, Veeck L, Rosenwaks Z. Fertility preservation in breast cancer patients: ivf and embryo cryopreservation after ovarian stimulation with tamoxifen. Hum Reprod 2003;18:90–5.
cross-ref  pubmed  

119. Checa Vizcaino MA, Corchado AR, Cuadri ME, Comadran MG, Brassesco M, Carreras R. The effects of letrozole on ovarian stimulation for fertility preservation in cancer-affected women. Reprod Biomed Online 2012;24:606–10.
cross-ref  pubmed  

120. Oktay K, Kan MT, Rosenwaks Z. Recent progress in oocyte and ovarian tissue cryopreservation and transplantation. Curr Opin Obstet Gynecol 2001;13:263–8.
cross-ref  pubmed  

121. Gosden RG, Baird DT, Wade JC, Webb R. Restoration of fertility to oophorectomized sheep by ovarian autografts stored at –196 degrees C. Hum Reprod 1994;9:597–603.
pubmed  

122. Aubard Y. Ovarian tissue xenografting. Eur J Obstet Gynecol Reprod Biol 2003;108:14–18.
cross-ref  pubmed  

123. Shaw JM, Bowles J, Koopman P, Wood EC, Trounson AO. Fresh and cryopreserved ovarian tissue samples from donors with lymphoma transmit the cancer to graft recipients. Hum Reprod 1996;11:1668–73.
cross-ref  pubmed  

124. Kim SS, Radford J, Harris M, et al. Ovarian tissue harvested from lymphoma patients to preserve fertility may be safe for autotransplantation. Hum Reprod 2001;16:2056–60.
cross-ref  pubmed  

125. Foulkes WD, Shuen AY. In brief: BRCA1 and BRCA2. J Pathol 2013;230:347–9.
cross-ref  pubmed  

126. Oktay K, Buyuk E, Rosenwaks Z, Rucinski J. A technique for transplantation of ovarian cortical strips to the forearm. Fertil Steril 2003;80:193–8.
cross-ref  pubmed  

127. Oktay KH, Yih M. Preliminary experience with orthotopic and heterotopic transplantation of ovarian cortical strips. Semin Reprod Med 2002;20:63–74.
cross-ref  pubmed  

128. Oktay K, Economos K, Kan M, Rucinski J, Veeck L, Rosenwaks Z. Endocrine function and oocyte retrieval after autologous transplantation of ovarian cortical strips to the forearm. JAMA 2001;286:1490–3.
cross-ref  pubmed  

129. Oktay K. Ovarian tissue cryopreservation and transplantation: preliminary findings and implications for cancer patients. Hum Reprod Update 2001;7:526–34.
cross-ref  pubmed  

130. Oktay K, Karlikaya G. Ovarian function after transplantation of frozen, banked autologous ovarian tissue. N Engl J Med 2000;342:1919.
cross-ref  pubmed  

131. Baird DT, Webb R, Campbell BK, Harkness LM, Gosden RG. Long-term ovarian function in sheep after ovariectomy and transplantation of autografts stored at –196°C. Endocrinology 1999;140:462–71.
pubmed  

132. Donnez J, Dolmans MM, Demylle D, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet 2004;364:1405–10. [Erratum in: Lancet 2004;364:2020]
cross-ref  pubmed  

133. Silber SJ, DeRosa M, Pineda J, et al. A series of monozygotic twins discordant for ovarian failure: ovary transplantation (cortical versus microvascular) and cryopreservation. Hum Reprod 2008;23:1531–7.
cross-ref  pubmed  

134. Ernst E, Bergholdt S, Jorgensen JS, Andersen CY. The first woman to give birth to two children following transplantation of frozen/thawed ovarian tissue. Hum Reprod 2010;25:1280–1.
cross-ref  pubmed  

135. Sanchez-Serrano M, Crespo J, Mirabet V, et al. Twins born after transplantation of ovarian cortical tissue and oocyte vitrification. Fertil Steril 2010;93:268.e11–3.
cross-ref  

136. Demeestere I, Simon P, Buxant F, et al. Ovarian function and spontaneous pregnancy after combined heterotopic and orthotopic cryopreserved ovarian tissue transplantation in a patient previously treated with bone marrow transplantation: case report. Hum Reprod 2006;21:2010–14.
cross-ref  pubmed  

137. Roux C, Amiot C, Agnani G, Aubard Y, Rohrlich PS, Piver P. Live birth after ovarian tissue autograft in a patient with sickle cell disease treated by allogeneic bone marrow transplantation. Fertil Steril 2010;93:2413.e15–19.
cross-ref  

138. Andersen CY, Rosendahl M, Byskov AG, et al. Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissue. Hum Reprod 2008;23:2266–72.
cross-ref  pubmed  

139. Bedaiwy MA, Falcone T. Whole ovary transplantation. Clin Obstet Gynecol 2010;53:797–803.
cross-ref  pubmed  

140. Arav A, Natan Y. Directional freezing: a solution to the methodological challenges to preserve large organs. Semin Reprod Med 2009;27:438–42.
cross-ref  pubmed  

141. Courbiere B, Caquant L, Mazoyer C, Franck M, Lornage J, Salle B. Difficulties improving ovarian functional recovery by microvascular transplantation and whole ovary vitrification. Fertil Steril 2009;91:2697–706.
cross-ref  

142. Bromer JG, Patrizio P. Fertility preservation: the rationale for cryopreservation of the whole ovary. Semin Reprod Med 2009;27:465–71.
cross-ref  pubmed  

143. Ives A, Saunders C, Bulsara M, Semmens J. Pregnancy after breast cancer: population based study. BMJ 2007;334:194.
cross-ref  pmc  

144. Blakely LJ, Buzdar AU, Lozada JA, et al. Effects of pregnancy after treatment for breast carcinoma on survival and risk of recurrence. Cancer 2004;100:465–9.
cross-ref  pubmed  

145. Helewa M, Levesque P, Provencher D, et al. Breast cancer, pregnancy, and breastfeeding. J Obstet Gynaecol Can 2002;24:164–80.
pubmed  

146. Gelber S, Coates AS, Goldhirsch A, et al. on behalf of the International Breast Cancer Study Group. Effect of pregnancy on overall survival after the diagnosis of early-stage breast cancer. J Clin Oncol 2001;19:1671–5.
pubmed  

147. Han SS, Kim YH, Lee SH, et al. Underuse of ovarian transposition in reproductive-aged cancer patients treated by primary or adjuvant pelvic irradiation. J Obstet Gynaecol Res 2011;37:825–9.
cross-ref  pubmed  

148. Mazonakis M, Damilakis J, Varveris H, Gourtsoyiannis N. Radiation dose to laterally transposed ovaries during external beam radiotherapy for cervical cancer. Acta Oncol 2006;45:702–7.
cross-ref  pubmed  

149. Bisharah M, Tulandi T. Laparoscopic preservation of ovarian function: an underused procedure. Am J Obstet Gynecol 2003;188:367–70.
cross-ref  pubmed  

150. Al-Badawi IA, Al-Aker M, AlSubhi J, et al. Laparoscopic ovarian transposition before pelvic irradiation: a Saudi tertiary center experience. Int J Gynecol Cancer 2010;20:1082–6.
cross-ref  pubmed  

151. Pahisa J, Martinez-Roman S, Martinez-Zamora MA, et al. Laparoscopic ovarian transposition in patients with early cervical cancer. Int J Gynecol Cancer 2008;18:584–9.
cross-ref  pubmed  

152. Morice P, Juncker L, Rey A, El-Hassan J, Haie-Meder C, Castaigne D. Ovarian transposition for patients with cervical carcinoma treated by radiosurgical combination. Fertil Steril 2000;74:743–8.
cross-ref  pubmed  

153. Nguyen L, Brewer CA, DiSaia PJ. Ovarian metastasis of stage IB1 squamous cell cancer of the cervix after radical parametrectomy and oophoropexy. Gynecol Oncol 1998;68:198–200.
cross-ref  pubmed  

154. Picone O, Aucouturier JS, Louboutin A, Coscas Y, Camus E. Abdominal wall metastasis of a cervical adenocarcinoma at the laparoscopic trocar insertion site after ovarian transposition: case report and review of the literature. Gynecol Oncol 2003;90:446–9.
cross-ref  pubmed  

155. Morris SN, Ryley D. Fertility preservation: nonsurgical and surgical options. Semin Reprod Med 2011;29:147–54.
cross-ref  pubmed  

156. Williams RS, Littell RD, Mendenhall NP. Laparoscopic oophoropexy and ovarian function in the treatment of Hodgkin disease. Cancer 1999;86:2138–42.
cross-ref  pubmed  

157. Ronn R, Holzer HE. Oncofertility in Canada: the impact of cancer on fertility. Curr Oncol 2013;20:e338–44.
cross-ref  pubmed  pmc  

158. Ronn R, Holzer HE. Oncofertility in Canada: an overview of Canadian practice and suggested action plan. Curr Oncol 2013;20:e465–74.
cross-ref  pubmed  pmc  


Correspondence to: Jeff Roberts, Pacific Centre for Reproductive Medicine, 500–4601 Canada Way, Burnaby, British Columbia V5G 4X7. E-mail: jroberts@pacificfertility.ca

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Current Oncology, VOLUME 22, NUMBER 4, August 2015








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ISSN: 1198-0052 (Print) ISSN: 1718-7729 (Online)