Faculty Bibliography

OBJECTIVE:To evaluate socioeconomic, demographic, and medical factors that influence the referral pattern-either before cancer treatment for fertility preservation (FP, early referral) or post-chemotherapy for assisted reproductive technology (PCART, delayed referral)-in women with breast cancer. DESIGN/METHODS:Secondary analysis. SETTING/METHODS:Academic medical centers. PATIENT(S)/METHODS:Three hundred fourteen patients with breast cancer who were counseled for FP (n=218) or PCART (n=96) from June 1999 to July 2009. INTERVENTION(S)/METHODS:None. MAIN OUTCOME MEASURE(S)/METHODS:Factors favoring early referrals. RESULT(S)/RESULTS:Mean age at diagnosis was higher in FP vs. PCART (35.3±4.5 years vs. 33.9±4.7 years). Ninety percent presented with cancer stage 1 or 2. From 2000 to 2009 the proportion of referrals for FP increased continually. In 2009, nearly all (95.5%) were for FP. The majority (63.8%) was referred from an academic center. Patients with a family history of breast cancer were more likely to consult for FP (75.2% vs. 64.3% without). There was no association with occupation, income, race, ethnicity, obstetric history, and prior infertility treatment. Only 22.9% of those counseled in PCART, compared with 45.0% in the FP group, proceeded with a procedure. CONCLUSION(S)/CONCLUSIONS:There has been an increasing trend within the last 10 years for early referral of breast cancer patients to FP. Factors favoring early referrals are older age, early-stage cancer, family history of breast cancer, and academic center involvement. Those seen before cancer treatment are more likely to receive an intervention.

Ovarian transplantation is one of the key approaches to restoring fertility in women who became menopausal as a result of cancer treatments. A major limitation of human ovarian transplants is massive follicular loss during revascularization. Here we investigated whether sphingosine-1-phosphate or its receptor agonists could enhance neoangiogenesis and follicle survival in ovarian transplants in a xenograft model. Human ovarian tissue xenografts in severe-combined-immunodeficient mice were treated with sphingosine-1-phosphate, its analogs, or vehicle for 1-10 days. We found that sphingosine-1-phosphate treatment increased vascular density in ovarian transplants significantly whereas FTY720 and SEW2871 had the opposite effect. In addition, sphingosine-1-phosphate accelerated the angiogenic process compared to vehicle-treated controls. Furthermore, sphingosine-1-phosphate treatment was associated with a significant proliferation of ovarian stromal cell as well as reduced necrosis and tissue hypoxia compared to the vehicle-treated controls. This resulted in a significantly lower percentage of apoptotic follicles in sphingosine-1-phosphate-treated transplants. We conclude that while sphingosine-1-phosphate promotes neoangiogenesis in ovarian transplants and reduces ischemic reperfusion injury, sphingosine-1-phosphate receptor agonists appear to functionally antagonize this process. Sphingosine-1-phosphate holds great promise to clinically enhance the survival and longevity of human autologous ovarian transplants.

c-Jun N-terminal kinase (JNK) pathway has been shown to be essential for cell cycle progression and mitosis. We previously showed that this pathway is activated in mitotic granulosa cells of follicles from transitional to antral stages. In this study, we, therefore, aimed to investigate whether this signaling pathway has any effect on in-vitro growth of murine preantral follicles and granulosa cell cycle control. Two structurally different pharmacologic JNK inhibitors, SP600125 and AS601245, were used in the experiments. First their inhibitory concentrations were determined in granulosa cells by Western blot analysis. Then preantral follicles isolated from immature and adult C57BL/6 mice were cultured in matrigel and standard culture plates for 6 days with these inhibitors. Spontaneously immortalized rat granulosa cells (SIGCs) were first synchronized at G1/S and G2/M stages of cell cycle and then treated with JNK inhibitors. Cell cycle progression was analyzed with Bromodeoxyuridine (BrdU) assay and flow cytometry analysis. Both inhibitors significantly inhibited phosphorylation of c-Jun in granulosa cells at 25, 50, and 100 μmol/L concentrations. Isolated preantral follicles cultured with these inhibitors exhibited arrested growth in culture in a dose-dependent manner. Cell cycle analyses showed that both inhibitors impair the progression of cell cycle at S phase and G2/M transition of granulosa cells. These results suggest that JNK pathway is essential for in vitro growth of preantral follicle growth and regulates both S phase and G2/M stages of cell cycle in granulosa cells.

OBJECTIVE:To report the long-term follow-up of an experimental heterotopic ovarian transplantation with frozen-thawed ovarian tissue. DESIGN/METHODS:Long-term follow-up of an experimental surgery; case report. SETTING/METHODS:Academic reproductive medicine center. PATIENT(S)/METHODS:A 28-year-old cancer survivor with previous Hodgkin disease and relapse. INTERVENTION(S)/METHODS:Laparoscopic oophorectomy for ovarian cryopreservation before preconditioning chemotherapy for hematologic stem cell transplantation. Ovarian tissue thawing and subcutaneous heterotopic ovarian transplantation in the lower abdominal wall 2½ years after the hematologic stem cell transplantation. MAIN OUTCOME MEASURE(S)/METHODS:Resumption of ovarian function after transplantation, recovery of fertility, and pregnancy outcome. RESULT(S)/RESULTS:Follicle development was observed in the graft 2 months after transplantation, and a P value of 14 ng/mL indicated ovulation. The patient conceived spontaneously four times within 5 years and delivered three children. The in situ ovary remained atrophic but showed occasional follicle activity contemporaneously with the graft. CONCLUSION(S)/CONCLUSIONS:The mechanism behind spontaneous restoration of fertility with consecutive viable pregnancies after a heterotopic ovarian transplantation needs to be explored. Further laboratory and clinical research will be needed to explore the true origin of pregnancies after ovarian transplantations.

Imatinib mesylate is the first in a family of highly effective, minimally toxic, targeted agents used widely to treat Philadelphia-positive leukemias and selected other cancers, leading to a steady rise in the prevalence of patients using such therapy. Because failure of therapy would require conventional gonadotoxic chemotherapeutics, many female patients using imatinib may choose to preserve fertility. Herein, we provide evidence of a potential negative effect of imatinib on ovarian function by reporting the first case of a woman who showed a severely compromised ovarian response to gonadotropin stimulation while on imatinib, with a normal ovarian response after stopping this medication.

Fertility preservation is an important issue for young women diagnosed with breast cancer. The most well-established options for fertility preservation in cancer patients, embryo and oocyte cryopreservation, have not been traditionally offered to breast cancer patients as estradiol rise during standard stimulation protocols may not be safe for those patients. Potentially safer stimulation protocols using tamoxifen and aromatase inhibitors induce lower levels of estradiol whereas similar results in terms of number of oocyte and embryo obtained to standard protocols. Cryopreservation of immature oocytes and ovarian cortical tissue, both still experimental methods, are also fertility preservation options for breast cancer patients.

PURPOSE/OBJECTIVE:To determine whether early referral to reproductive specialists improves fertility preservation (FP) outcomes and reduces delay in adjuvant treatment in young women with breast cancer. PATIENTS AND METHODS/METHODS:A secondary analysis of a prospective database of patients with breast cancer undergoing ovarian stimulation (OS) for FP by oocyte or embryo cryopreservation was performed. RESULTS:Of the 154 patients, 93 met the inclusion criteria (mean age, 35.2 ± 4.4 years). Thirty-five of the 93 patients were referred before breast surgery (PreS), and 58 patients were referred after surgery (PostS). The time periods from initial diagnosis (ID) to initiation of OS (42.6 ± 27.7 days for PreS v 71.9 ± 30.7 days for PostS; P < .001) and from ID to initiation of chemotherapy (83.9 ± 24.3 days for PreS v 107.8 ± 42.9 days for PostS; P = .045) were significantly shorter for the PreS group versus the PostS group. Nine (25.7%) of 35 patients in the PreS group versus one (1.7%) of 58 patients in the PostS group were able to undergo two FP cycles (P < .001), resulting in an increased yield of oocytes in the PreS group (18.2% [93 of 511 oocytes] v 0.6% [five of 800 oocytes], respectively; P < .001) and embryos (17.2% [40 of 233 embryos] v 0.6% [two of 357 embryos], respectively; P < .001). Patients who had an oocyte retrieval within 5 weeks of the surgery were able to complete a second cycle within 9 weeks of the surgery. CONCLUSION/CONCLUSIONS:FP referral before breast surgery enables earlier initiation of cryopreservation cycles and chemotherapy and, when appropriate, multiple FP cycles. Women who can undergo multiple cycles may be at advantage for FP because of a larger number of oocytes or embryos cryopreserved. This is the first study demonstrating the benefit of early FP referral in patients with cancer.

We describe a preliminary report identifying markers of ovarian reserve to identify candidates for ovarian cryopreservation. Among 14 patients with Turner's syndrome, those with a poor probability of fertility had a significantly higher FSH, lower inhibin A, and lower AMH compared with those with a fair probability of fertility.

Demographic data and tumour characteristics of 18 patients (study group) diagnosed with breast cancer within 24 months of undergoing ovarian stimulation with either gonadotrophins or clomiphene citrate were evaluated and compared with similar 102 age-matched women diagnosed with breast cancer without prior infertility treatment (control group). Eight out of 17 (47.1%) patients in the study group and 35/95 (36.8%) patients in the control group had positive family history for breast cancer. Median tumour size was similar in the study and control groups (both 1.3 cm). Both groups were comparable regarding tumour histological types and oestrogen receptor, progesterone receptor and Her2/Neu expression status. Albeit not significant, stage 0 tumours were more prevalent in the study group compared with the control group (22.2% versus 10.5%), and there were no stage III tumours in the study group as opposed to 7/95 in the control group. In conclusion, breast cancer diagnosed within the first 2 years following infertility treatment is similar in tumour characteristics compared with those occurring in patients without prior infertility treatment.