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Every year, an increasing number of women with malignant and nonmalignant diseases is successfully treated with cytotoxic chemotherapy and/or radiotherapy. Many of these patients suffer from infertility and gonadal failure as a result of these treatments. At present, these patients may resort to assisted-reproduction techniques to protect their future childbearing potential before the implementation of cytotoxic therapy. While embryo cryopreservation is an established technology, oocyte and ovarian tissue freezing techniques are still investigational. Nevertheless both of these techniques have resulted in live births. Apart from assisted-reproduction techniques, it has been extensively debated whether administration of gonadotropin-releasing hormone (GnRH) analogues in conjunction with chemotherapy can protect ovarian reserve against cytotoxic insult. In this manuscript, we debate the rationale for the effectiveness of GnRH analogue coadministration in preservation of fertility by reviewing the literature, and provide preliminary data to support our views.

CONTEXT/BACKGROUND:Women with breast cancer are not typically offered embryo or oocyte cryopreservation to preserve their fertility before chemotherapy because of the potential risks associated with high estrogen levels arising from ovarian stimulation. OBJECTIVE:We aimed to determine whether the combination of an aromatase inhibitor with gonadotropin treatment in breast cancer patients produces comparable results to standard in vitro fertilization (IVF), without a significant increase in estradiol levels and delay in the initiation of chemotherapy. PATIENTS AND METHODS/METHODS:Stages I-IIIA breast cancer patients (n = 47) received 5 mg/d letrozole and 150-300 IU FSH to cryopreserve embryos or oocytes. Age-matched retrospective controls (n = 56) were selected from women who underwent IVF for tubal disease. RESULTS:Whereas letrozole and FSH stimulation resulted in significantly lower peak estradiol levels (mean +/- sd 483.4 +/- 278.9 vs. 1464.6 +/- 644.9 pg/ml; P < 0.001) and 44% reduction in gonadotropin requirement, compared with controls, the length of stimulation, number of embryos obtained, and fertilization rates were similar. The human chorionic gonadotropin administration criteria had to be adjusted to 20 mm after letrozole stimulation, compared with 17-18 mm in the controls. The mean delay from surgery to cryopreservation was 38.6 d, with 81% of all patients completing their IVF cycles within 8 wk of surgery. CONCLUSION/CONCLUSIONS:Ovarian stimulation with letrozole and FSH appears to be a cost-effective alternative for fertility preservation in breast cancer patients with reduced estrogen exposure, compared with standard IVF. If patients are referred promptly, they may undergo embryo or oocyte cryopreservation without a delay in chemotherapy.

OBJECTIVE:To determine the efficiency of oocyte cryopreservation relative to IVF with unfrozen oocytes. DESIGN/METHODS:Meta-analysis. SETTING/METHODS:Academic assisted reproduction center. PATIENT(S)/METHODS:Results of all reports from January 1997 to June 2005 with the patients undergoing IVF-intracytoplasmic sperm injection (ICSI) with cryopreserved cycles between 1996 and 2004 were compared with those of patients who underwent IVF-ICSI with unfrozen oocytes in 2002 and 2003 in our program. INTERVENTION(S)/METHODS:Mean age and number of ET cycles originating from unfrozen oocytes was matched with those for thaw cycles originating from oocytes cryopreserved with a slow-freezing (SF) protocol. Vitrification (VF) reports were not included in the comparative analysis because of a small number of pregnancies (10) before June 2005. MAIN OUTCOME MEASURE(S)/METHODS:The comparison of fertilization rate, clinical pregnancy, and live-birth rates per injected oocyte, clinical pregnancy and live-birth rates per transfer, and implantation rate between IVF-ICSI cycles with frozen and unfrozen oocytes. RESULT(S)/RESULTS:Live-birth rates per oocyte thawed were 1.9% and 2.0% for SF and VF, respectively, before June 2005. Live-birth rates per injected oocyte and ET, respectively, were 3.4% and 21.6% for SF and were 6.6% and 60.4% for IVF with unfrozen oocytes. Compared to women who underwent IVF after SF, IVF with unfrozen oocytes resulted in significantly better rates of fertilization (odds ratio [95% confidence interval]); 2.22 (1.80, 2.74), of live birth per injected oocyte; 1.5 (1.26, 1.79), and of implantation; 4.66 (3.93, 5.52). These odds ratios were lower when oocyte cryopreservation success rates from 2002-2004 were compared with those for IVF with unfrozen oocytes. When the reports after June 2005 were considered, this trend did not appear to continue. With the consideration of VF reports after June 2005, however, higher pregnancy rates were achieved. CONCLUSION(S)/CONCLUSIONS:In vitro fertilization success rates with slow-frozen oocytes are significantly lower when compared with the case of IVF with unfrozen oocytes. Although oocyte cryopreservation with the SF method appears to be justified for preserving fertility when a medical indication exists, its value for elective applications remains to be determined. Pregnancy rates with VF appear to have improved, but further studies will be needed to determine the efficiency and safety of this technique.

Breast cancer accounts for one third of all neoplasms seen in reproductive-age women and affects tens of thousands of women each year in that age group. The adjuvant chemotherapy regimens used for the treatment commonly affect fertility and cause premature ovarian failure. There have been recent advances in the field of fertility preservation, which can allow many of these breast cancer survivors to have children in the future. The most established option is embryo cryopreservation; oocyte cryopreservation can be considered in single women. Both of these approaches require approximately 2 weeks of ovarian stimulation beginning with the onset of the patient's menstrual cycle. Thus, it is crucial that these patients are referred to appropriate assisted reproduction centers as soon as they are diagnosed with breast cancer. Recently developed ovarian stimulation protocols using tamoxifen and letrozole can be used to increase the margin of safety in these patients. When and if a breast cancer patient does not have time to undergo ovarian stimulation prior to chemotherapy, ovarian cryopreservation for future autotransplantation can be offered as the last resort. The benefit of ovarian protection by gonadotropin-releasing hormone analogues is unproven and unlikely, and thus this treatment should not be offered as the sole method of fertility preservation.

PURPOSE/OBJECTIVE:To develop guidance to practicing oncologists about available fertility preservation methods and related issues in people treated for cancer. METHODS:An expert panel and a writing committee were formed. The questions to be addressed by the guideline were determined, and a systematic review of the literature from 1987 to 2005 was performed, and included a search of online databases and consultation with content experts. RESULTS:The literature review found many cohort studies, case series, and case reports, but relatively few randomized or definitive trials examining the success and impact of fertility preservation methods in people with cancer. Fertility preservation methods are used infrequently in people with cancer. RECOMMENDATIONS/CONCLUSIONS:As part of education and informed consent before cancer therapy, oncologists should address the possibility of infertility with patients treated during their reproductive years and be prepared to discuss possible fertility preservation options or refer appropriate and interested patients to reproductive specialists. Clinician judgment should be employed in the timing of raising this issue, but discussion at the earliest possible opportunity is encouraged. Sperm and embryo cryopreservation are considered standard practice and are widely available; other available fertility preservation methods should be considered investigational and be performed in centers with the necessary expertise. CONCLUSION/CONCLUSIONS:Fertility preservation is often possible in people undergoing treatment for cancer. To preserve the full range of options, fertility preservation approaches should be considered as early as possible during treatment planning.

Ovarian cryopreservation and transplantation is an emerging technology to preserve fertility in women and children undergoing cancer treatment. Recent reports of live births after orthotopic transplantation raised hopes for the future success of this procedure. However, doubts remained whether the reported pregnancies were as a result of resumed function in the remaining ovary. We recently performed an autologous heterotopic ovarian transplantation in a 32-year-old Hodgkin lymphoma survivor who was menopausal for 2.5 years as a result of a preconditioning chemotherapy given before a hematopoietic stem cell transplant. Subsequent to the transplantation, the patient conceived twice within 3 months and delivered a healthy female child at 40 weeks of gestation. The occurrence of spontaneous pregnancies after heterotopic ovarian transplantation highlights the need for caution when interpreting the source of pregnancies in recipients with intact ovaries. On the other hand, the temporal relationship between the ovarian transplant and the spontaneous resumption of ovarian function and pregnancies in previously menopausal women is intriguing, especially in the light of recent reports of germ cell renewal and migration from the bone marrow to the ovary in rodents.

Modern treatments for cancers of the reproductive age are yielding ever-higher cure rates, but more often than not, the price paid for survival is the loss of reproductive function from gonadal toxicity. Alkylating agents and ionizing radiation have well-recognized deleterious effects within the testes and ovary and cause sterility in a high proportion of patients exposed to these treatments. Preservation of fertility for men simply involves the banking of sperm before treatment, but for women, the storage of gametes is technically very complex and has limited success. Even when faced with the diagnosis of cancer, many reproductive-aged women are burdened by the possibility of never conceiving a child with their own eggs. Fertility preservation for the reproductive-age women with cancer is emerging as a challenging, but rewarding, application of assisted reproductive technologies such as in vitro fertilization. With recent advances in cryopreservation techniques, oocytes, embryos, and ovarian tissue can be banked from these patients before exposure to sterilizing chemotherapy and radiotherapy, providing future fertility options without compromising survival.