Faculty Bibliography

BACKGROUND:The authors sought to describe the age-specific impact of infertility and early menopause after chemotherapy among reproductive age women with cancer. METHODS:A total of 1041 women diagnosed with cancer between the ages of 18 and 40 years responded to a retrospective survey on reproductive health history. Five cancer types were included: leukemia, Hodgkin disease (HD), non-Hodgkin lymphoma (NHL), breast cancer, and gastrointestinal(GI) cancer. Survey questions addressed acute ovarian failure (cessation of menses after treatment), early menopause (menopause before 45 years old), and infertility (failed conception). Logistic regression was used to determine the proportions of acute ovarian failure and infertility based on age at diagnosis. Censored data methods were used to determine the probability of early menopause. RESULTS:Six hundred twenty women received chemotherapy alone. The percentage reporting acute ovarian failure was 8%, 10%, 9%, and 5% for HD, NHL, breast cancer, and GI cancer, respectively. Acute ovarian failure increased significantly with age at diagnosis (P < .05). In subjects not reporting acute ovarian failure, the incidence of infertility was at least 40% at age 35 years and increased significantly with age at diagnosis in HD and breast cancer (P < .05). The estimated probability of early menopause was at least 25% at age 30 years and increased significantly with younger age at diagnosis in HD, NHL, and GI cancer (P < .05). CONCLUSIONS:For patients to receive appropriate counseling, it is important that they understand the potential increased risk of infertility and early menopause beyond that of acute ovarian failure. These findings can provide improved, age-specific counseling regarding reproductive impairment for young women diagnosed with cancer.

Options for preserving fertility in women include well-established methods such as fertility-sparing surgery, shielding to reduce radiation damage to reproductive organs, and emergency in-vitro fertilisation after controlled ovarian stimulation, with the aim of freezing embryos. The practice of transfering frozen or thawed embryos has been in place for over 25 years, and today is a routine clinical treatment in fertility clinics. Oocytes may also be frozen unfertilised for later thawing and fertilisation by intracytoplasmic sperm injection in vitro. In recent years, oocyte cryopreservation methods have further developed, reaching promising standards. More than 1000 children are born worldwide after fertilisation of frozen and thawed oocytes. Nevertheless, this technique is still considered experimental. In this chapter, we focus on options for fertility preservation still in development that can be offered to women. These include freezing of oocytes and ovarian cortex and the transplantation of ovarian tissue.

Women with breast cancer face many challenges when considering fertility preservation. Delayed referral results in the limitation of fertility preservation options because most established methods, such as embryo and oocyte cryopreservation, require several weeks to complete. Women with BRCA mutations, on the other hand, may be more aware of fertility issues and motivated to see fertility preservation specialists earlier. Fear of exposure to estrogen limits access to fertility preservation via embryo or oocyte cryopreservation; however, the use of aromatase inhibitors as ovarian stimulants reduces such concern. Ovarian cryopreservation can be used when there is insufficient time to perform ovarian stimulation because this technique does not require hormonal stimulation, but there are safety concerns both in women with BRCA mutations and in patients with hormone receptor-positive disease as well. There does not seem to be a proven ovarian suppression strategy to preserve fertility in women with breast cancer. Pregnancy appears to be safe for breast cancer survivors but studies specific for women with BRCA mutations are lacking. Women with BRCA mutations may elect to use preimplantation genetic diagnosis during in vitro fertilization to avoid transmitting the mutation, but there may be psychosocial difficulties in entertaining this option. Overall, the last decade has brought many options for women with breast cancer considering fertility preservation, but numerous challenges remain. The presence of BRCA mutations further contributes to these challenges.

OBJECTIVE:To evaluate the efficacy of ovarian stimulation with higher doses of gonadotropins in fertility preservation (FP) cycles with the intention to maximize the likelihood of future pregnancies. DESIGN/METHODS:Retrospective (secondary analysis). SETTING/METHODS:Academic medical centers. PATIENT(S)/METHODS:Low-dose (LD, 150 IU; n = 34) versus high-dose (HD, >150 IU; n = 117) FSH start in 151 patients with breast cancer (BCa) undergoing ovarian stimulation for embryo cryopreservation with letrozole (LE) before cancer treatment. INTERVENTION(S)/METHODS:None. MAIN OUTCOME MEASURE(S)/METHODS:FP cycle outcomes. RESULT(S)/RESULTS:Mean total FSH dose (2,037 ± 679 IU vs. 1,128 ± 381 IU) and FSH level on trigger day (21.1 ± 8.9 vs. 10.6 ± 4.5 mIU/mL) were higher in the HD group, confirming the receipt of higher-dose FSH. There was no difference in other patient characteristics. Despite the larger number of follicles >17 mm in diameter in the HD group (5.0 ± 2.0 vs. 3.4 ± 1.4), neither peak E(2) (498.0 ± 377.5 vs. 397.9 ± 320.3), number of oocytes (13.3 ± 8.7 vs. 12.3 ± 8.0), nor number of embryos (6.3 ± 4.7 vs. 5.4 ± 3.8) were significantly different from the LD group. Of those undergoing frozen embryo transfer (ET), live birth rate (LBR)/ET trended higher in the LD (9/15) compared with HD (2/11) group, with 2.1 ± 0.8 vs. 1.9 ± 0.3 embryos transferred, respectively. CONCLUSION(S)/CONCLUSIONS:Higher-dose FSH stimulation in LE cycles does not improve outcomes and may be associated with lower LBR. Our findings may support minimal stimulation in young noninfertile women with BCa.

OBJECTIVE:To evaluate predictors of undergoing fertility preservation treatment (FPT) in women with breast cancer. DESIGN/METHODS:Secondary analysis of a clinical database. SETTING/METHODS:Three academic fertility preservation centers. PATIENT(S)/METHODS:One hundred eight patients with breast cancer undergoing FPT and 77 patients with breast cancer not undergoing FPT from 2005 to 2010. INTERVENTION(S)/METHODS:None. MAIN OUTCOME MEASURE(S)/METHODS:Patients' demographic and medical information. RESULT(S)/RESULTS:Women who had FPT were older, wealthier, and had lower cancer stage compared with women who did not have FPT. The rate of the administration of neoadjuvant chemotherapy (NAC) was significantly lower in women who underwent FPT. After adjusting for age, body mass index (BMI), income, cancer stage, and center, a negative correlation persisted between NAC and FPT (odds ratio 0.091, 95% confidence interval 0.009-0.904). When we stratified the women by center, women at center 1 had a significantly lower FPT rate, lower parity, higher BMI, more advanced cancer stage, and lower income compared with centers 2 and 3. The rates of NAC were significantly higher in center 1. CONCLUSION(S)/CONCLUSIONS:Although age, BMI, income, cancer stage, center, and NAC seem to be associated with undergoing FPT, NAC is the only modifiable variable. Because NAC restricts the time available for FPT, oncologists may consider offering adjuvant chemotherapy, except in cases in which NAC clearly improves survival, in women who are interested in FPT.

Breast cancer is the most common malignancy diagnosed in women in the United States. Many breast cancer survivors are concerned that cancer treatment will compromise their reproductive potential. Despite this concern, most women receive limited information addressing preservation of fertility before initiating adjuvant chemotherapy. Historically, the supraphysiologic levels of estrogens associated with ovarian stimulation have precluded the use of assisted reproductive technologies in the presence of breast cancer. In an effort to mitigate the potential effects of elevated estrogen levels during ovulation induction, we developed a novel ovarian stimulation protocol for women with breast cancer, with the use of aromatase inhibitors. Our studies suggest that in the short term, aromatase inhibitors plus gonadotropins are safe and effective agents for ovarian stimulation in fertility preservation cycles. In this review, we outline the data supporting the use of aromatase inhibitors for ovarian hyperstimulation in women with breast cancer before initiating adjuvant chemotherapy.

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.

OBJECTIVE:To report an emergency approach of random-start controlled ovarian hyperstimulation (COH) in the late follicular or luteal phase of the menstrual cycle for embryo cryopreservation in patients with cancer. DESIGN/METHODS:Case series. SETTING/METHODS:Academic tertiary referral centers. PATIENT(S)/METHODS:Three patients with a diagnosis of breast cancer requiring emergency fertility preservation in the late follicular or luteal phase of the menstrual cycle. INTERVENTION(S)/METHODS:After baseline pelvic ultrasound and hormonal evaluation, random-start COH was commenced immediately on menstrual cycle days 11, 14, or 17 with use of letrozole 2.5 mg/d and recombinant FSH 150 to 300 IU/d. Gonadotropin-releasing hormone antagonist was administered to prevent ovulation in all cases. Ovulation was triggered with either 250 μg of recombinant hCG or 10,000 IU of urinary hCG. MAIN OUTCOME MEASURE(S)/METHODS:Number of oocytes harvested, maturity and fertilization rates, number of embryos frozen. RESULT(S)/RESULTS:Nine to 17 oocytes were harvested, resulting in the freezing of seven to 10 embryos with the mean maturity and fertilization rates of 58.8% to 77.7% and 69.2% to 87.5%, respectively. CONCLUSION(S)/CONCLUSIONS:In an emergent setting, ovarian stimulation can be started at a random cycle date for the purpose of fertility preservation without compromising fertilization rates in letrozole cycles.

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.