Faculty Bibliography

With recent advances in cryobiology, cryopreservation of the oocyte and ovarian tissue is rapidly becoming an important service provided by medical centers throughout the world. The general indication for oocyte or ovarian tissue cryopreservation is to retain future fertility potential for women who face the possibility of premature or imminent ovarian failure resulting from treatments for various disease states including cancer. Considering limitations imposed by age, lack of a partner, or sufficient time to undergo embryo cryopreservation, these patients have few options if they desire preservation of their fertility. The objective of this manuscript is to review the basic aspects of oocyte and ovarian tissue cryopreservation, and to discuss the current and future applications of these technologies in fertility preservation.

PURPOSE/OBJECTIVE: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/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/CONCLUSIONS: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.

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.