Kutluk Oktay

Context: 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: 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: 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.

Purpose: To develop safe ovarian stimulation methods to perform in vitro fertilization (IVF) in breast cancer patients who wish to preserve their fertility via embryo cryopreservation before chemotherapy. Patients and Methods: Sixty women (age range, 24 to 43 years) with breast cancer were prospectively studied. Twenty-nine patients underwent 33 ovarian stimulation cycles with either tamoxifen 60 mg/d alone (Tam-IVF) or in combination with low-dose follicle-stimulating hormone (TamFSH-IVF) or letrozole 5 mg in combination with FSH (Letrozole-IVF). After IVF, all resultant embryos were cryopreserved to preserve fertility. Recurrence rates were compared with controls (n = 31) who elected not to undergo IVF. Results: Compared with Tam-IVF, both TamFSH-IVF and Letrozole-IVF patients had greater numbers of follicles (2 ± 0.3 v 6 ± 1 and 7.8 ± 0.9, respectively; P < .0001), mature oocytes (1.5 ± 0.3 v 5.1 ± 1.1 and 8.5 ± 1.6, respectively; P < .001), and embryos (1.3 ± 0.2 v 3.8 ± 0.8 and 5.3 ± 0.8, respectively; P < .001). Peak estradiol (E₂) levels were lower with Letrozole-IVF and Tam-IVF compared with TamFSH-IVF. After 554 ± 31 days (range, 153 to 1,441 days) of follow-up, cancer recurrence rate was similar between IVF and control patients (three of 29 v three of 31 patients, respectively; hazard ratio, 1.5; 95% CI, 0.29 to 7.4), and this estimate was not affected by cancer stage. Conclusion: The combination of low-dose FSH with tamoxifen (TamFSH-IVF) or letrozole (Letrozole-IVF) results in higher embryo yield compared with Tam-IVF. Recurrence rates do not seem to be increased, but the letrozole protocol may be preferred because it results in lower peak E₂ levels.

An increasing number of women have been subjected to cytotoxic chemoradiotherapy for various malignant and nonmalignant diseases. Women who face the possibility of premature or imminent ovarian failure caused by cytotoxic therapy may retain their fertility potential with ovarian tissue cryopreservation. Until recently, this technique could only be performed in a few highly specialized institutions. However, with the latest advances in cryobiology, ovarian tissue cryopreservation is rapidly becoming a more widely offered technique by many medical centers around the world. The indications now extend beyond cancer. Even though the risk of reimplanting pre-existing cancer cells is minimal or non-existent for most types of cancer, this risk needs to be ascertained according to the cancer type and disease stage. The objective of this manuscript is to review the indications, risks and benefits of ovarian tissue cryopreservation.

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.

The growth control mechanism of early-stage ovarian follicles is unknown. Tyrosine phosphorylation of signaling molecules and changes in expression and activation of AP-1 transcription factors have been implicated in growth regulation of numerous cell types. In this study, we used immunohistochemistry to analyze tyrosine phosphorylation patterns and expression and activation of selected AP-1 transcription factors in mouse ovarian follicles. The ovaries were collected from B62F1/J mice in estrus. Representative sections were immunostained for phosphotyrosine, phospho-c-Jun, Jun D, and c-Fos. Phosphotyrosine staining was perioocytic from the transitional stage until approximately 5 to 7 layers of granulosa cells had formed. Perioocytic staining was then replaced by scattered stippled staining in granulosa cells of larger follicles. Phospho c-Jun was exclusively expressed in mitotic granulosa cells of follicles from transitional to antral stages. Jun D was expressed in the oocytes of primordial, primary, or transitional follicles and disappeared at the 2-layer preantral stage. Fos was present in corpora lutea and theca cells but not in granulosa cells. Collectively, these data indicate that phosphotyrosine signaling and AP-1 transcription factors are intimately involved in early stages of ovarian follicle growth.

In the USA alone, >650 000 women will be afflicted by cancer in 2003, and 8% of these cases will be aged <40 years. Due to improvements in cancer therapy, cure rates of both adult and childhood cancers increased significantly over the past three decades. However, long‐term consequences of cancer therapy and impact on quality of life are now being recognized. One of the major sequelae of cytotoxic chemotherapy is gonadal failure. Cytotoxic chemotherapy and/or radiotherapy are not only used to treat malignant diseases, but also non‐malignant systemic conditions. Upon reviewing the extent and mechanism of gonadal damage due to chemo‐/radiotherapy, this article discusses indications and the wide range of methods of fertility preservation in a comprehensive manner. All current, emerging, experimental as well as controversial approaches are reviewed. A comprehensive algorithm to manage fertility preservation through an individualized approach is presented.