Ralph R. Kazer

Fertility preservation for female cancer patients: early clinical experience

OBJECTIVE To characterize the early experience of a clinical program designed to provide strategies for fertility preservation to female cancer patients about to undergo chemotherapy or radiation therapy. DESIGN Retrospective chart review; case-control study. SETTING Academic medical center. PATIENT(S) Sixty-five female cancer patients and 57 age-matched infertility patients. INTERVENTION Enrollment in a program for fertility preservation. MAIN OUTCOME MEASURE(S) Choice of active participation, fertility preservation option selection, clinical outcomes of patients undergoing oocyte retrieval, attitudes regarding embryo disposition. RESULT(S) Of 65 patients referred to the program, 18 declined to undergo embryo, oocyte, or tissue cryopreservation. Six were found not to be eligible for medical reasons. Of the remaining 41 patients, 35 chose to cryopreserve embryos, four chose to cryopreserve oocytes, and two chose to undergo ovarian tissue freezing. Fewer oocytes were recovered from the embryo cryopreservation group when compared with an age-matched control group, but the mean number of zygotes generated was similar. Attitudes regarding embryo disposition were different between the two groups. No serious clinical sequelae resulted from participation. CONCLUSION(S) Fertility preservation techniques employing available technology may provide safe and practical options to female cancer patients facing chemotherapy or radiation therapy. A significant number of otherwise appropriate participants decline active management. Cancer patients display different attitudes regarding embryo disposition when compared with infertility patients without cancer.

Relationship between peak serum estradiol levels and treatment outcome in in vitro fertilization cycles after embryo transfer on day 3 or day 5

OBJECTIVE To examine the relationships between peak serum estradiol (E(2)) levels and treatment outcome in in vitro fertilization (IVF) cycles after embryo transfer (ET) on day 3 or day 5. DESIGN Retrospective analysis of 697 IVF-ET cycles between January 1999 and December 2001. SETTING A university-affiliated assisted reproduction program. PATIENT(S) Infertile patients undergoing IVF-ET cycles. INTERVENTION(S) Peak E(2) concentration in serum was determined on the day of human chorionic gonadotropin (hCG) administration. The IVF-generated embryos were cultured for 2 days until transfer on day 3. If more than four 8-cell embryos were present on day 3, embryo culture was continued until day 5 for blastocyst transfer. MAIN OUTCOME MEASURE(S) Clinical pregnancy rates. RESULT(S) High peak E(2) levels did not adversely affect treatment outcome. After the cycles were divided according to the day of ET, high peak E(2) levels were associated with improved pregnancy rates after ET on day 5 but not on day 3. CONCLUSION(S) Increasing peak E(2) levels in IVF cycles are associated with improved pregnancy rates after ET on day 5.

The Disposition of Unused Frozen Embryos

To the Editor: The disposition of unused embryos is a pressing problem for in vitro fertilization programs.1,2 Although cryopreservation of embryos gives couples the chance to make additional attem...

Serum insulin, insulin-like growth factor-I, and insulin-like growth factor binding protein-1 in women who develop preeclampsia

Objective To determine whether second-trimester serum concentrations of insulin, insulin-like growth factor-I (IGF-I), and insulin-like growth factor binding protein-1 (IG-FBP-1) were altered in women before they developed clinical signs of preeclampsia. Methods A nested case-control study used serum obtained during second-trimester pregnancies from 12 women who developed preeclampsia matched with 24 controls who remained normotensive. Nine preeclamptic subjects and 18 controls were necessary to have 80% power to discern a 20% difference between groups with regard to the analytes under consideration. Results There were no significant differences between cases and controls with respect to many demographic factors. Women who developed preeclampsia had insulin concentrations that were not significantly different from controls, but serum concentrations of IGF-I were significantly higher and IGFBP-1 were significantly lower than those of the controls. The IGF-I/IGFBP-1 ratio helped to identify those at risk for developing preeclampsia. Conclusions Serum concentrations of IGF-I and IGFBP-1 were abnormal long before women manifested clinical evidence of preeclampsia in this study. These alterations might be related to abnormalities in trophoblastic invasion and prove useful as potential markers for the identification of women who are at high risk of developing preeclampsia.

Sequential, randomized trial of a low‐fat, high‐fiber diet and soy supplementation: Effects on circulating IGF‐I and its binding proteins in premenopausal women

Despite evidence supporting the involvement of the IGF system in the development of breast and other cancers, the major determinants of interindividual variability in circulatory IGF‐I levels are not well understood. Previous research has pointed to important genetic influences as well as dietary effects through marked calorie or protein restriction. We conducted a randomized trial to determine the effects of 2 dietary patterns on serum IGF‐1, IGFBP1 and IGFBP3 in free‐living premenopausal women: phase 1, an isocaloric low‐fat, high‐fiber (LFHF) vs. usual diet, and phase 2, a soy supplement either with or without isoflavones (soy+IF vs. soy–IF). Participants completed 12 menstrual cycles on phase 1 and then were randomly assigned to a soy supplement for 3 cycles while maintaining the phase 1 diet. Before and after each phase, 154 women provided serum. We found no difference in the change in IGF‐I, BP1 or BP3 in the LFHF group compared to the usual diet group. In phase 2, there were no differences in any IGF protein between the soy+IF and the soy–IF groups or any evidence of interaction between isoflavone exposure and the background diet. However, there was a small but statistically significant decrease (2.3%) in BP3 and an increase in the IGF‐I:BP3 molar ratio among all 153 subjects following either soy supplement. These changes were correlated with changes in intake of calcium, total vegetable protein and soy. The results are compatible with previous data suggesting that increases in dietary calcium, protein and soy, in particular, could increase circulating levels of bioavailable IGF‐I.

Delay of embryo transfer to day 5 results in decreased initial serum β-human chorionic gonadotropin levels

OBJECTIVE To investigate the impact of delaying the transfer of in vitro fertilized embryos to day 5 on embryo development by comparing serum beta-hCG levels in pregnancies established after day 3 embryo transfers and those after day 5 blastocyst transfers at equivalent time intervals after fertilization. DESIGN A retrospective analysis. SETTING Assisted reproductive technology center in an academic research environment. PATIENT(S) Women who had an embryo transfer procedure performed after in vitro fertilization (IVF) at Northwestern Universitys IVF Program between January 1999 and December 2001 were included in this study. INTERVENTION(S) Embryo transfer was performed either on day 3 or day 5 after oocyte retrieval for IVF (day 0), depending on the availability of good-quality embryos on day 3. MAIN OUTCOME MEASURE(S) Serum beta-hCG concentrations determined 13 and 15 days after fertilization in pregnancies established by transferring cleavage-stage embryos on day 3 or blastocysts on day 5. RESULT(S) In singleton pregnancies, serum beta-hCG concentrations were 75 +/- 54 (mean +/- SD, n = 203) or 62 +/- 41 (n = 109) IU/mL after day 3 or day 5 transfers, respectively. In twin pregnancies, the beta-hCG concentrations were 162 +/- 105 (n = 52) or 109 +/- 55 (n = 49) after day 3 or day 5 transfers, respectively. The percentage increases in beta-hCG concentrations between the first and second measurements were similar in the two groups (day 3: 144 +/- 109, day 5: 142 +/- 63, not statistically significant). CONCLUSION(S) Initial beta-hCG concentrations in pregnancies resulting from day 5 transfers were lower than those from day 3 transfers when assessed at equivalent intervals from fertilization. This suggests that embryo development or implantation may be impaired by the additional 2 days in culture.

Oncofertility Consortium Consensus Statement: Guidelines for Ovarian Tissue Cryopreservation

In vitro fertilization (IVF) and storage of the resulting embryos is currently a proven method of fertility preservation for women who face an immediate threat to their future fertility. This method, however, is suitable for a fraction of patients and depends on a number of factors that may include her diagnosis, age, partner status, willingness to accept donor sperm, desire to freeze embryos, and ability to pay for these services. As fertility preservation techniques evolve, it is critical that physicians continue to evaluate practice guidelines in order to offer a wider menu of fertility preservation options tailored to each patient’s specific clinical scenario, to the risk-benefit ratio and takes into consideration the patient’s values. Practice guidelines and consensus statements for fertility preservation for oncology patients reflect the current evidence based and ethical practices in the related disciplines of oncology and reproductive endocrinology. Both the American Society of Clinical Oncology (ASCO) and the American Society of Reproductive Medicine (ASRM) recently published guidelines to describe the circumstances under which fertility preservation should be discussed and to describe patients for which experimental methods, such as ovarian cryopreservation, may be suitable [1–3]. Taken together, these documents are comprehensive in their description of: 1. The need for discussion with patients about impaired fertility resulting from cancer treatment,

Preoperative serum hCG level and intraoperative failure of laparoscopic linear salpingostomy for ectopic pregnancy.

Objective To identify factors that predict failure of linear salpingostomy requiring salpingectomy for ectopic pregnancy. Methods Using a retrospective cohort, we examined the various risk factors of women with ectopic pregnancies presenting for conservative laparoscopic management. Success or failure of laparoscopic linear salpingostomy was the primary end point. Results One hundred fifty-seven women underwent laparoscopic linear salpingostomy for ectopic pregnancy, of whom 120 had successful procedures and 36 had unsuccessful operations because of bleeding and needed subsequent salpingectomy either by laparoscopy or laparotomy. The likelihood of success of laparoscopic linear salpingostomy was unrelated to gestational age, size of the ectopic pregnancy, surgical technique, or experience of the surgeon or resident. However, median (quartiles) serum beta hCG levels were significantly higher in patients who underwent failed salpingostomy (10,103 [3549-19, 962] IU/L) compared with those who underwent successful salpingostomy (1692 [565-3971] IU/L, P < .01). Median blood loss (225 [181-562] mL versus 100 [50-200] mL, respectively, P < .01) and mean (± standard error of the mean [SEM]) operating times (111.1 ± 6.1 minutes versus 76.8 ± 2.3 minutes, P < .01) were significantly greater with failed salpingostomy followed by salpingectomy, compared with successful salpingostomy. Conclusion Preoperative serum beta hCG level was the only significant determinant of failure of laparoscopic linear salpingostomy for ectopic pregnancy. Morbidity due to intraoperative blood loss and operating time was significantly increased as a result of attempting and failing to complete laparoscopic linear salpingostomy.

Depletion of luteal phase serum progesterone during constant infusion of cortisol phosphate in the cynomolgus monkey

OBJECTIVE To study the impact of chronic infusions of cortisol phosphate on ovarian function in the cynomolgus monkey. DESIGN Cortisol phosphate at doses of 5 or 15 mg/d or saline were infused for periods of up to 8 weeks using subcutaneously implanted osmotic pumps. SETTING Animals were maintained in the Center for Experimental Animal Resources, Northwestern University. MAIN OUTCOME MEASURES Serum total and unbound cortisol concentrations, serum total and unbound progesterone (P) concentrations, urinary P metabolites. RESULTS Mean increases in serum cortisol of 56% and 77% above control levels were achieved. Mean serum P concentrations were not decreased with low-dose cortisol phosphate infusion during the 12 days preceding menses, but mean serum P levels were decreased by 69% to 2.3 ng/mL during high-dose cortisol phosphate infusion. No corresponding decrease in excretion of conjugated immunoreactive P metabolites was found in daily urine samples during cortisol phosphate infusion, suggesting that production rates of P were unaltered by the cortisol phosphate treatment. Unbound serum cortisol increased by a mean of 162% above control levels during high-dose cortisol phosphate infusion, but no increase occurred in the percentage of unbound serum P. CONCLUSIONS We conclude that elevation of serum cortisol in the range observed in chronically stressed individuals may severely decrease the available P to target organs by displacement of P from plasma proteins but does not inhibit ovarian steroidogenesis or ovulation.

Fertility preservation outcomes may differ by cancer diagnosis

CONTEXT: Cancer survival has improved significantly and maintaining fertility is both a major concern and an important factor for the quality of life in cancer patients. AIMS: To explore differences in oocyte stimulation for fertility preservation (FP) patients based on cancer diagnosis. SETTINGS AND DEIGN: Between 2005 and 2011, 109 patients elected to pursue FP at a single institution. MATERIALS AND METHOD: In vitro fertilization (IVF) outcome variables between four cancer diagnostic groups (breast, gynecologic, lymphoma/leukemia and other) and age-matched male factor or tubal factor infertility IVF control group were compared. STATISTICAL ANALYSIS: ANOVA and Chi-square analyses were employed to compare variables between the groups that were normally distributed. Kruskal–Wallis with subsequent Mann–Whitney U-test were used for data that were not normally distributed. RESULTS: Women with gynecologic malignancies were significantly older than the women in the other three groups, but tended to have a better ovarian response. Women with hematologic malignancies were most likely to have been exposed to chemotherapy and had the longest stimulations with a similar number of oocytes retrieved. The age-matched IVF controls had higher peak estradiol levels, number of oocytes obtained, and fertilization rates when compared to cancer patients with or without a history of prior chemotherapy. CONCLUSIONS: Factors including age, type of cancer and chemotherapy exposure, can influence response to ovarian stimulation. Discussing these findings with patients presenting for FP may aid in setting realistic treatment expectations.