Faculty Bibliography

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.

Infertility following treatment of cancer is a quality of survival's recognized issue and efforts should be made to help young cancer patients retaining their fertility potential. Options to preserve fertility in female patients include well established methods such as shielding to reduce radiation damage to reproductive organs, fertility-sparing surgery and emergency in vitro fertilization after controlled ovarian stimulation, aiming at freezing embryos. Transfer of frozen/thawed embryos today is a clinical routine in fertility clinics worldwide and it has been used for over 25 years. Mature oocytes after ovarian stimulation can also be frozen unfertilized, nevertheless overall pregnancy rates after fertilization of frozen-thawn oocytes are still relatively lower than those with embryo freezing. Remaining fertility preservation options are still in development and include the freezing of immature oocytes aiming at later in vitro maturing and fertilizing them and the cryopreservation of ovarian tissue for future retransplantation or for in vitro growth and maturation of follicles, both still experimental.

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.

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.

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.

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.

The mechanism of chemotherapy-induced acceleration of ovarian aging is not fully understood. We used doxorubicin, a widely used cancer chemotherapeutic, in a variety of in vivo xenograft, and in vitro models to investigate the impact of chemotherapy-induced aging on the human ovary. Doxorubicin caused massive double-strand-DNA-breaks in primordial follicles, oocytes, and granulosa cells in a dose dependent fashion as revealed by accumulating γH2AX foci. This damage was associated with apoptotic oocyte death and resulted in the activation of ATM. It appeared that the repair response enabled a minor proportion of oocytes (34.7%) and granulosa cells (12.1%) to survive while the majority succumbed to apoptotic death. Paradoxically, inhibition of ATM by KU-55933 resulted in improved survival, probably via prevention of downstream activation of TAp63α. Furthermore, doxorubicin caused vascular and stromal damage in the human ovary, which might impair ovarian function both pre- and post-menopausally. Chemotherapy-induced premature ovarian aging appears to result from a complex process involving both the germ- and non-germ cell components of the ovary. These effects may have clinical implications in aging both for premenopausal and postmenopausal cancer survivors.

PURPOSE/OBJECTIVE:To predict embryo/oocyte cryopreservation cycle (ECC) outcomes in breast cancer patients stimulated with letrozole and follicle stimulating hormone for fertility preservation based on observed anti-mullerian hormone (AMH) levels and antral follicle counts (AFC). METHODS:The correlation between AMH and AFC and ECC outcomes were analyzed retrospectively on forty one women with breast cancer before adjuvant treatment. RESULTS:AMH and AFC had a stronger correlation with the total number of oocytes and the number of mature oocytes than age, FSH, and inhibin B. Subjects were evaluated by the number of mature oocytes retrieved to create cutoff points of AMH level, which identified 1.2 ng/mL as a potential value. Seven of 18 patients with AMH levels ≤1.2 ng/mL had low response versus none of 23 with >1.2 ng/mL, (p = 0.001). CONCLUSIONS:AMH is the most reliable serum marker of ECC outcomes, together with AFC as a biophysical marker, in breast cancer patients. Low response is highly likely when the AMH level is ≤1.2 ng/mL.

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.