Gonadatrophin suppression to prevent chemotherapy-induced ovarian damage: a randomized controlled trial.

OBJECTIVE: To estimate the effectiveness of gonadotropin-releasing hormone (GnRH) analogues cotreatment in preventing chemotherapy-induced amenorrhea in young breast cancer patients undergoing cyclophosphamide-based chemotherapy. METHODS: One hundred hormone-insensitive breast cancer participants (aged 18-40 years) were recruited from two university-affiliated oncology centers in Egypt. Opting for type of cotreatment was based on available timeframe until start of chemotherapy. Fifty women ready for early chemotherapy were randomized to receive either chemotherapy alone (arm I) or chemotherapy after downregulation (estradiol less than 50 pg/mL) by GnRH antagonist and agonist (arm II). Then, GnRH antagonist was discontinued and agonist was continued until the end of chemotherapy. When chemotherapy was to start later than 10 days after study inclusion, 50 women were randomized to receive either chemotherapy alone (arm III) or chemotherapy after downregulation with GnRH agonist (arm IV). Resumption of menstruation at 12 months after end of chemotherapy was the primary outcome. Postchemotherapy hormonal and ultrasound changes were secondary outcomes. RESULTS: Twelve months after termination of chemotherapy, there were no differences in menstruation resumption rates between GnRH-treated patients and control group individuals in either early (80% in arms I and II, risk ratio 1, 95% confidence interval 0.7-.32; P=1.00) or delayed chemotherapy groups (80% and 84% in arms III and IV, risk ratio 0.95, 95% confidence interval 0.73-1.235; P=.71). There were no differences in hormonal and ultrasound markers between GnRH analogue users and control group individuals. The use of GnRH analogue cotreatment did not predict independently the odds of menstruating at 12 months. CONCLUSION: GnRH analogue cotreatment does not offer a significant protective effect on ovarian function in patients treated by cyclophosphamide-based chemotherapy. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry. www.anzctr.org.au, ACTRN12609001059257. LEVEL OF EVIDENCE: I.

Blastocyst-stage versus cleavage-stage embryo transfer in women with high oestradiol concentrations: randomized controlled trial.

This prospective, randomized, controlled trial tested the hypothesis that delaying embryo transfer to the blastocyst stage can increase the probability of clinical pregnancy and live birth in women with high oestradiol concentrations on the day of human chorionic gonadotrophin (HCG) undergoing intracytoplasmic sperm injection using the long protocol. A total of 200 women with oestradiol >3000 pg/ml on the HCG day with four or more good-quality, day-3 embryos were randomized in a 1:1 ratio to undergo day-3 or day-5 embryo transfer. Clinical pregnancy rates (CPR; 41% versus 59%; relative risk 0.70, 95% CI 0.52­0.93) and ongoing pregnancy/live-birth rates (35% versus 52%; relative risk 0.67, 95% CI 0.46­0.93) were lower in women undergoing cleavage-stage than blastocyst-stage embryo transfer. Using receiver operating characteristic curves, among women undergoing cleavage-stage embryo transfer, a detrimental cut-off value for not achieving pregnancy for oestradiol was 4200 pg/ml, with lower CPR and ongoing pregnancy/live-birth rates (P = 0.006 and 0.02, respectively). No detrimental cut-off value for oestradiol was identified among women undergoing blastocyst-stage embryo transfer. Delaying embryo transfer to the blastocyst stage can increase the probability of pregnancy in women with high oestradiol on the HCG day

Progesterone level and progesterone/estradiol ratio on the day of hCG administration: detrimental cutoff levels and new treatment strategy.

OBJECTIVE: To identify if there are certain cutoff levels for P and or the P/E(2) ratio on the day of hCG that would be defined as detrimental for occurrence of pregnancy in women with normal ovarian reserve undergoing cleavage-stage embryo transfer (ET). Secondarily, to determine if these same cutoffs might have the same potential negative effect in women undergoing blastocyst ET. DESIGN: Prospective cohort study including two randomized cohorts. SETTING: Private and university fertility centers. PARTICIPANT(S): A total of 240 women undergoing long agonist protocol with at least four grade 1 day 3 embryos. INTERVENTION(S): Women were randomized in a 1:1 ratio to undergo day 3 or day 5 embryo transfer. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (CPR) was the primary outcome. RESULT(S): Using receiver operator characteristics, cutoffs for P and P/E(2) ratio were 1.5 ng/mL and 0.55, respectively. Patients with P ≤ 1.5 ng/mL and P/E(2) ≤ 0.55 undergoing cleavage-stage ET had higher CPR. Using multiple regression, P/E(2) ratio was the only independent predictor for pregnancy. The P and P/E(2) cutoffs were not correlated with CPR in blastocyst transfers. CONCLUSION(S): Progesterone >1.5 ng/mL and P/E(2) >0.55 affect the CPR in women undergoing cleavage-stage, but not blastocyst ET. P/E(2) ratio is the only independent prognosticator for cycle outcome in women undergoing cleavage-stage ET.

N-acetyl cysteine: could it be an effective adjuvant therapy in ICSI cycles? A preliminary study.

This randomized controlled trial tested the hypothesis that addition of N-acetyl cysteine (NAC) can increase the probability of pregnancy in intracytoplasmic sperm injection (ICSI) cycles using the long agonist protocol. Women undergoing ICSI cycles due to male factor were randomly assigned to receive either long protocol (group A, 38 women) or long protocol plus NAC (group B, 38 women). Clinical pregnancy was the primary outcome. Granulosa cell apoptosis, fertilization rate, number of grade-one embryos and ongoing pregnancy were the secondary outcomes. Clinical pregnancy rate was insignificantly higher in NAC group (52.6%) than control (47.4%). Early and late apoptosis were also insignificantly lower in group B than in group A. Irrespective of the used protocol, there was significant negative correlation between both early and late apoptosis and fertilization rate (both P<0.001) and the number of good-quality embryos (P=0.007 and P<0.001, respectively). Pregnant patients had significantly lower early and late apoptosis than those who didn't achieve pregnancy (P<0.001). In conclusion, NAC supplementation did not significantly increase the probability of pregnancy in ICSI cycles using long agonist protocol. It appears that granulosa cell apoptosis may be an important prognosticator for ICSI cycle outcome.

Does luteal estradiol supplementation have a role in long agonist cycles?

OBJECTIVE: To test the hypothesis that the addition of 6 mg estradiol (E2) valerate either orally or vaginally to progesterone (P) for luteal support, can increase the probability of pregnancy in intracytoplasmic sperm injection (ICSI) cycles using the long agonist protocol. DESIGN: Prospective open-labeled randomized controlled trial. SETTING: Private and university fertility centers. PARTICIPANT(S): Women undergoing ICSI cycles, with controlled ovarian hyperstimulation using long agonist protocol. INTERVENTION(S): On embryo transfer day, participants were randomized to receive, only P (group A, n = 90), P along with 6 mg E(2) valerate either orally (group B, n = 90), or vaginally (group C, n = 90) for luteal support. MAIN OUTCOME MEASURE(S): Clinical pregnancy was the main outcome. luteal serum E(2) and P profiles were the secondary outcomes. RESULT(S): Highest pregnancy rate was achieved in group C (45.56%), it was significantly higher than A (relative risk 1.52, 95% CI: 1.03 to 2.24). Day 0 (hCG day) E2 levels were similar in the three groups. Group A had lower E2 levels on days 7, 10, and 13 and a higher magnitude of E2 decline on days 7 and 10. Similar levels of luteal E2 were documented in groups B and C. P levels were similar in the three groups. CONCLUSIONS(S): Addition of 6 mg E(2) valerate to P support may encumber the sharp decline in luteal E(2) level. It may enhance the probability of pregnancy if administered vaginally.

Anti-Müllerian hormone: correlation of early follicular, ovulatory and midluteal levels with ovarian response and cycle outcome in intracytoplasmic sperm injection patients.

OBJECTIVE: To measure serum anti-Müllerian hormone (AMH) during different phases of the menstrual cycle and to correlate the measurements with ovarian response and clinical-pregnancy rates in intracytoplasmic sperm injection cycles. DESIGN: Prospective cohort study. SETTING: University IVF unit. PATIENT(S): Thirty-three patients undergoing their first intracytoplasmic sperm injection treatment cycle with a long protocol. INTERVENTION(S): On day 3 of the menstrual cycle, measurements of AMH, FSH, and LH and ultrasound evaluation of mean ovarian volume and antral follicle count were performed. Anti-Müllerian hormone was remeasured at ovulation and 7-8 days later (midluteal). MAIN OUTCOME MEASURE(S): Poor response and number of oocytes were primary outcomes. Clinical pregnancy was a secondary outcome. RESULT(S): Levels of AMH were lower in poor ovarian responders than in normal responders. Number of oocytes retrieved was statistically significantly correlated with midluteal AMH, day 3 AMH, antral follicle count, ovulatory AMH, mean ovarian volume (r = 0.89, 0.88, 0.88, 0.86, 0.66, respectively) and with day 3 FSH (r = -0.41). Midluteal, day 3, and ovulatory AMH showed a good discriminatory potential for prediction of poor response (area under the receiver operating characteristics curves, 0.977, 0.9, and 0.89, respectively). Midluteal and early AMH were statistically significant predictors of clinical pregnancy. CONCLUSION(S): A strong association exists between midluteal, early follicular, ovulatory AMH levels and number of oocytes retrieved. Midluteal and early follicular AMH may offer good prognostic value for clinical pregnancy.