Antonio Requena

Use of letrozole in assisted reproduction: a systematic review and meta-analysis

BACKGROUND Letrozole is the third-generation aromatase inhibitor (AI) most widely used in assisted reproduction. AIs induce ovulation by inhibiting estrogen production; the consequent hypoestrogenic state increases GnRH release and pituitary follicle-stimulating hormone (FSH) synthesis. METHODS A systematic search of the literature was performed for both prospective and retrospective studies. Meta-analyses of randomized clinical trials (RCTs) were performed for three comparisons: letrozole versus clomiphene citrate (CC), letrozole + FSH versus FSH in intrauterine insemination (IUI) and letrozole + FSH versus FSH in IVF. In the absence of RCTs, non-randomized studies were pooled. RESULTS Nine studies were included in the meta-analysis. Four RCTs compared the overall effect of letrozole with CC in patients with polycystic ovary syndrome. The pooled result was not significant for ovulatory cycles (OR = 1.17; 95% CI 0.66–2.09), or for pregnancy rate per cycle (OR = 1.47; 95% CI 0.73–2.96) or for pregnancy rate per patient (OR = 1.37; 95% CI 0.70–2.71). In three retrospective studies which compared L + FSH with FSH in ovarian stimulation for IUI, the pooled OR was 1.15 (95% CI 0.78−1.71). A final meta-analysis included one RCT and one cohort study that compared letrozole + gonadotrophin versus gonadotrophin alone: the pooled pregnancy rate per patient was not significantly different (OR = 1.40; 95% CI 0.67–2.91). CONCLUSIONS Letrozole is as effective as other methods of ovulation induction. Further randomized-controlled studies are warranted to define more clearly the efficacy and safety of letrozole in human reproduction.

Transabdominal ultrasound-guided embryo transfer does not increase pregnancy rates in oocyte recipients

OBJECTIVE To determine whether transabdominal ultrasound guidance during embryo transfer (ET) is a useful tool for increasing pregnancy rates in patients undergoing oocyte donation. DESIGN Prospective, randomized, controlled trial. SETTING In vitro fertilization academic center. PATIENT(S) Three hundred seventy-four infertile patients undergoing oocyte donation. INTERVENTION(S) Transabdominal ultrasound-guided ET. MAIN OUTCOME MEASURE(S) We measured the pregnancy rate and implantation rate after transabdominal ultrasound-guided ET versus the rates in a control group who did not receive transabdominal ultrasound-guided ET. RESULT(S) Clear visualization at ultrasound during ET was achieved in 90.8% of the patients who had ultrasound-guided ET. A similar number of easy transfers were performed in both the ultrasound-guided and the control groups (84.5% vs. 86.6%). The pregnancy rate was comparable between the groups (59.9% ultrasound vs. 55.1% control), as was the implantation rate (30.6% ultrasound vs. 26.3% control). No differences were found in the miscarriage rate (10.7% ultrasound vs. 9.1% control) or in the multiple pregnancy rate (21.4% ultrasound vs. 22.5% control). Although all ectopic pregnancies occurred in the group that did not receive ultrasound guidance, the differences were not statistically significant (0 vs. 2.7%). CONCLUSION(S) We could not show any benefit in terms of pregnancy rate in oocyte recipients for whom ET was performed under direct transabdominal ultrasound visualization of the endometrial cavity. There was a lower ectopic pregnancy rate when ultrasound guidance was used, but this rate was not statistically significant in comparison with the pregnancy rate without ultrasound guidance.

Cycle scheduling with oral contraceptive pills in the GnRH antagonist protocol vs the long protocol: a randomized, controlled trial

OBJECTIVE To compare cycle outcomes after scheduling with the standard long protocol versus the use of oral contraceptive pills (OCPs) in patients undergoing GnRH antagonist cycles. DESIGN Prospective, randomized, controlled trial. SETTING University-affiliated private assisted reproduction center. PATIENT(S) Regularly cycling women aged ≤38 years with fewer than three previous IVF attempts were enrolled. Previous low responses to controlled ovarian hyperstimulation, ovarian surgery, or polycystic ovary were exclusion criteria. INTERVENTION(S) One hundred fifteen patients received OCP (0.030 ethinyl E(2)/0.15 desogestrel) for 12-16 days, and controlled ovarian hyperstimulation was started on day 5 after OCP treatment; similarly, 113 patients received the long protocol from day 20-22 of the previous cycle. MAIN OUTCOME MEASURE(S) The primary outcome was ongoing pregnancy rate; secondary outcome variables were clinical pregnancy rate, live birth rate, implantation rate, and miscarriage rate. RESULT(S) Patients receiving the GnRH antagonist treatment showed a lower peak serum E(2) (1,334 vs. 1,823 pg/mL) but similar peak serum PE (0.58 vs. 0.65 ng/mL), lower duration of the stimulation (10.3 vs. 11.4 days) with similar FSH consumption (1,613 vs. 1,807 IU), and ovarian response (10.2 vs. 11.7 oocytes). No differences were observed in the fertilization rates (68.1% vs. 64.8%), total number of embryos obtained (5.9 vs. 6.2), mean number of embryos transferred (1.8 vs. 1.8), implantation rate (36% vs. 39%), miscarriage rate (8.9% vs. 17%), ongoing pregnancy rate (47.8% vs. 53.9%), or live birth rate (44.3% vs. 47%). CONCLUSION(S) Comparable outcomes can be obtained using OCP containing 0.030 ethinyl E(2)/0.15 desogestrel to schedule patients undergoing the antagonist protocol.

The impact of in-vitro maturation of oocytes on aneuploidy rate.

Chromosome abnormalities in embryos obtained through in-vitro maturation (IVM) of oocytes from 11 oocyte donors were compared with embryos from women undergoing fluorescence in-situ hybridization (FISH) analysis for sex selection. Thirty-three oocytes had reached metaphase II stage at 28-30 h (65%) and 27 were successfully fertilized by intracytoplasmic sperm injection. Blastomere biopsy was performed in 20 embryos (74%). For five embryos, two blastomeres were analysed, three of which were mosaic. FISH study revealed aneuploidies of chromosomes 13, 15, 16, 18, 21, 22, X and Y in 12 embryos (60%) and euploidy in the remaining eight (40%). The percentage of aneuploidies in the control group was 33%. Differences between IVM and control embryos were not statistically significant. The high incidence of chromosome abnormalities in embryos resulting from the IVM protocol may account for the low implantation rates reported by others. Although a greater incidence of miscarriage or congenital abnormalities in babies born alive following IVM versus conventional IVF has not been observed in previous studies, preimplantation genetic aneuploidy screening or prenatal chromosome studies may be recommended to these patients on the basis of the present results.

Extended coasting duration exerts a negative impact on IVF cycle outcome due to premature luteinization.

Coasting, or withholding gonadotrophin administration while maintaining gonadotrophin-releasing hormone analogue until oestradiol drops to a safe concentration, is an alternative approach to prevent ovarian hyperstimulation syndrome (OHSS) in high responder patients. However, the length of this procedure has not been precisely studied. This paper is a retrospective study of 132 patients who showed a high response (oestradiol > 4500 pg/ml and/or more than 20 follicles > 17 mm) to ovarian stimulation and were coasted due to their high risk of developing OHSS, and evaluated the impact of the duration of coasting on IVF cycle outcome. Additionally, serum LH and progesterone concentrations were studied to investigate whether premature luteinization was present in these cycles and whether it might be related to coasting duration. A significant decrease in implantation rate was found when coasting was required for more than 4 days, together with a trend towards a higher cancellation rate. Premature luteinization was significantly elevated in women undergoing coasting compared with control women (34 versus 15.6%, P < 0.05). In the majority of patients who showed premature luteinization, coasting lasted >/=3 days. To conclude, prolonged coasting may affect the endometrium, anticipating the implantation window. These data may explain why some women undergoing extended coasting show a lower implantation rate compared with controls.

Letrozole administration during the luteal phase after ovarian stimulation impacts corpus luteum function: a randomized, placebo-controlled trial

OBJECTIVE To investigate the effect of letrozole-an oral aromatase inhibitor-on E(2), P, and LH levels when administered during the luteal phase after oocyte retrieval in IVF/intracytoplasmic sperm injection (ICSI) cycles. DESIGN Prospective, randomized, placebo controlled trial. SETTING University-affiliated private reproductive medicine center. PATIENT(S) Thirty oocyte donors undergoing standardized controlled ovarian hyperstimulation (COH) protocols. INTERVENTION(S) Patients were randomized after successful egg retrieval to receive either 2.5 mg of letrozole (Femara; Novartis, Barcelona, Spain) or a placebo (folic acid tablets). All donors were under intrauterine device (IUD) contraception. MAIN OUTCOME MEASURE(S) Serum E(2), P, and LH the day of hCG administration and days +4, +7 and +10 after ovum pick-up. RESULT(S) Donors had a comparable serum E(2) level on the day of hCG administration (1,858 vs. 2,143 pg/mL). Interestingly, levels dramatically dropped 4 days after egg retrieval, reaching a statistically significant lower level in those receiving letrozole (279 vs. 1,586 pg/mL). Again, at the next time points serum E(2) levels were significantly lower (day +7: 240 vs. 855 pg/mL and day +10: 40 vs. 448 pg/mL). No significant differences were observed in P levels, but LH serum concentrations were lower in the control group on day +7 (0.18 vs. 0.02 mIU/mL and day +10 (0.40 vs. 0.16 mIU/mL), when serum E(2) levels were higher. CONCLUSION(S) The administration of 2.5 mg of letrozole during the luteal phase has an impact on corpus luteum (CL) function. It reduces serum E(2) levels, which allows a faster recovery of LH concentration. This may be of interest not only for egg donors, but also in patients at high risk of ovarian hyperstimulation syndrome (OHSS) who freeze all their embryos or who cancel hCG administration to reduce the potential risk that high E(2) levels pose.

Estradiol supplementation during the luteal phase of IVF-ICSI patients: a randomized, controlled trial

OBJECTIVE To evaluate the effectiveness of transdermal E(2) administration in the luteal phase of IVF/ICSI cycles. DESIGN Prospective, open-label, randomized clinical trial. SETTING University-affiliated assisted reproduction center. PATIENTS 1) Pilot trial to test serum E(2) behaviour during the luteal phase in women undergoing agonist as well as antagonist protocol; 2) women undergoing IVF/ICSI with good-quality embryos available. INTERVENTION(S) One hundred seventy-six patients were randomized by random number list on the day of embryo transfer to either: 1) progesterone (P) only as luteal support (200 mg bid starting the following night after oocyte retrieval); or 2) E(2) and P combined, applying E(2) patches (100 microg/day) twice per week beginning on the day of embryo transfer with P, as in the P-only group. MAIN OUTCOME MEASURE(S) The primary outcome was implantation rate per embryo transfer; secondary outcome variables were pregnancy rate per embryo transfer, early pregnancy loss, multiple pregnancy rate, and midluteal P and E(2) levels. RESULT(S) Hormonal levels did not differ between groups. There were no statistically significant differences in terms of implantation rate (34.9% [51 of 146] vs. 28.9% [41 of 142]), ongoing pregnancy rate 42% ([34 of 81] vs. 41.8% [33 of 79]), early pregnancy loss (15% [6 of 40] vs. 13.2% [5 of 38]), or multiple pregnancy rate (28.6% [12 of 42] vs. 24.4% [10/41]) in patients receiving P versus E(2) + P. CONCLUSION(S) The addition of transdermal E(2) to the luteal-phase P support of IVF cycles did not improve cycle outcomes in terms of implantation and pregnancy rates.

Acute leukemia during pregnancy: obstetric management and perinatal outcome of two cases

The coexistence of leukemia and pregnancy is extremely rare. This paper describes two cases of acute promyelocytic leukemia diagnosed during the second trimester of pregnancy and the most suitable approach to the management of this situation is analyzed. Possible teratogenic effects of mono- or polychemotherapy during pregnancy, depending upon the gestational age at which chemotherapy is given, are discussed.

Endocrine profile following stimulation with recombinant follicle stimulating hormone and luteinizing hormone versus highly purified human menopausal gonadotropin.

BackgroundLuteinizing hormone (LH) activity in human menopausal gonadotropin (hMG) preparations is derived from human chorionic gonadotropin (hCG) rather than LH. Therefore, we aimed to determine whether there are similarities in the endocrine and follicular profiles of serum and follicular fluid from controlled ovarian stimulation with the recombinant gonadotropins follicle-stimulating hormone plus luteinizing hormone (rFSH + rLH) or highly purified human menopausal gonadotropin (HP-hMG).MethodsWe performed a prospective observational study with 50 oocyte donors that received either a combination of recombinant gonadotropins (rFSH + rLH) or a mixture of urinary gonadotropins (HP-hMG) plus purified urinary FSH (uFSH). Results were analyzed using Student’s t-test to compare continuous variables and the chi-squared test to compare proportions. P-values < 0.05 were considered statistically significant.ResultsAlthough more oocytes were retrieved after treatment with recombinant than urinary gonadotropins (16.5 vs. 11.8; P = 0.049), a higher proportion of metaphase II ova (71.2% vs. 80.6%; P = 0.003) were obtained using urinary gonadotropins. On day 6 and on the day of triggering, serum steroid hormone levels were slightly but not significantly elevated in the recombinant group compared with the urinary group. In follicular fluid, no statistical differences were observed for intra-follicular levels of steroid hormones between the two protocols; ongoing pregnancy rates were similar (46.1% vs. 46.1%).ConclusionsOur data suggest that endocrinological and follicular profiles do not differ between rFSH + rLH and HP-hMG stimulation.

Evaluation of the degree of satisfaction in oocyte donors using sustained-release FSH corifollitropin α

Ovarian stimulation treatment is recognized as placing a physical and psychological burden on patients and oocyte donors. The introduction of sustained follicle stimulants will reduce the number of injections and may improve the overall patient experience. This study aimed to evaluate the degree of satisfaction in oocyte donors undergoing treatment with corifollitropin α, a synthetic recombinant rFSH which replaces daily FSH injections for the first week of ovarian stimulation. The results showed no significant differences in clinical parameters between the two protocols (recombinant FSH versus corifollitropin α). Implantation rates for the corifollitropin α and daily FSH protocol groups were 39.1% and 38.4%, respectively, while ongoing pregnancy rates were 45.9% and 44.4%. There were no statistical between-group differences in the responses to the questionnaires. However, donors treated with corifollitropin α who had undergone a previous cycle with daily FSH reported greater satisfaction with the corifollitropin α protocol. In conclusion, no significant differences were found in any analysed parameters between treatments. However, when donors who had undergone both treatments chose which treatment they preferred, the results clearly showed a positive trend towards choosing corifollitropin α, confirming that this protocol may reduce treatment burden and increase donor compliance.