Co-treatment with letrozole during ovarian stimulation for IVF/ICSI: a systematic review and meta-analysis

Bülow, Nathalie Søderhamn; Holt, Marianne Dreyer; Skouby, Sven O.; Petersen, Kathrine Birch; Englund, Anne Lis Mikkelsen; Pinborg, Anja; Macklon, Nicholas S.

doi:10.1016/j.rbmo.2021.12.006

Cited by 16 publications

(14 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The use of aromatase inhibitors in IVF patients remains controversial (Garcia-Velasco, 2012), and the data for letrozole cotreatment in high responders were quite limited in assisted reproductive technology cycles (Bulow et al, 2022). Our research demonstrated a superior implantation rate through letrozole cotreatment with the PPOS protocol in PCOS patients.…”

Section: Discussionmentioning

confidence: 56%

“…Currently, letrozole is widely used as an adjunct for IVF cycles (Yang et al, 2021). Cotreatment with letrozole during ovarian stimulation for IVF could significantly reduce gonadotropin consumption in normal and poor ovarian responders without decreasing the number of retrieved oocytes, some even accompanied by increased pregnancy outcomes, while few studies have focused on the clinical characteristics of letrozole coadministration in PCOS patients treated for IVF (Bulow et al, 2022;Jiang et al, 2022). The endocrine and ovulation induction characteristics of PCOS patients are different from those of normal and poor ovarian responders.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Letrozole cotreatment with progestin-primed ovarian stimulation in women with polycystic ovary syndrome undergoing IVF treatment

et al. 2022

View full text Add to dashboard Cite

Background: Progestin is an alternative to gonadotropin-releasing hormone (GnRH) analogues in the follicular phase to suppress the premature luteinizing hormone (LH) surge in women with polycystic ovary syndrome (PCOS). However, progestin-primed ovarian stimulation (PPOS) is always accompanied by increased pituitary suppression and gonadotropin consumption. Previous studies suggested that letrozole appeared to have the potential to reduce the total gonadotropin dose required for ovarian stimulation. A retrospective cohort study was performed to evaluate the efficacy of PPOS with or without letrozole in infertile women with PCOS.Methods: This retrospective cohort study included 448 women with PCOS who underwent controlled ovarian stimulation (COS) with human menopausal gonadotropin (hMG) and medroxyprogesterone acetate (MPA) (n = 224) or hMG and MPA cotreatment with LE (n = 224) from January 2018 to March 2021 after propensity-score matching. The primary outcome measure was the hMG dose. The secondary outcomes were the durations of ovarian stimulation, the implantation rate, the number of oocytes retrieved and viable embryos, oocyte maturity and fertilization rates, the percentage of women with profound pituitary suppression (luteinizing hormone [LH] <1.0 IU/L on the trigger day).Results: The hMG doses (1949.89 ± 725.03 IU vs 2017.41 ± 653.32 IU,p > 0.05) and durations of ovarian stimulation (9.03 ± 1.79 days vs 9.21 ± 2.18 days,p > 0.05) were similar between the two groups. The implantation rate was significantly higher in the study group (MPA + hMG + LE) than in the control group (MPA + hMG) (42.22 vs 34.69%, p < 0.05). The numbers of oocytes and embryos retrieved were similar between the two groups. Interestingly, letrozole cotreatment was associated with decreased oocyte maturity and fertilization rates in comparison with standard PPOS protocols even though mature and fertilized oocyte yields were comparable. Compared with those in the control group, the LH values on the trigger day were significantly higher in the study group, together with significantly reduced pituitary suppression.Conclusion: Letrozole combined with PPOS cannot reduce hMG consumption in PCOS patients undergoing IVF treatment and shows no beneficial effect on cycle characteristics of COS. However, letrozole supplementation manifests as a superior implantation rate to that of the standard PPOS protocol in women with PCOS.

show abstract

Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Letrozole cotreatment with progestin-primed ovarian stimulation in women with polycystic ovary syndrome undergoing IVF treatment

et al. 2022

View full text Add to dashboard Cite

show abstract

“…This explanation was also suggested in other studies, showing that much higher E2 levels were not favorable for implantation and pregnancy rates ( 5 , 6 ). Moreover, a more recent study demonstrated that no significant effect on LBR was found in normal responders with letrozole co-treatment reducing E2 level ( 34 ). This may be due to the fact that letrozole not only inhibits the production of estrogen, but also affects the recruitment of follicles neutralizing the negative impact of reduced E2 both through enhanced serum levels of gonadotrophins and because of the endogenous acidic isoform of FSH, which is lacking in the recombinant exogenous FSH ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

The Association Between Serum Estradiol Levels on hCG Trigger Day and Live Birth Rates in Non-PCOS Patients: A Retrospective Cohort Study

Yang

Yan

et al. 2022

Front. Endocrinol.

View full text Add to dashboard Cite

ObjectiveTo retrospectively analyze the association of serum estradiol (E2) levels on human chorionic gonadotropin (hCG) trigger day and live birth rates (LBRs) in women undergoing fresh embryo transfer and not exhibiting polycystic ovary syndrome.DesignRetrospective cohort study.MethodsAnalysis of 13,950 patients who had fresh embryo transfer between December 2013 and December 2019. The main outcome measurement was LBRs. Multivariable regression analysis was performed to investigate associations between E2 levels on the hCG trigger day and LBRs. Stratification analysis was performed to test for effect modification in subgroups. Furthermore, a two-piecewise linear regression model was established to find nonlinear relationships.ResultsMultivariable regression analysis showed a significant association between serum E2 levels on the hCG trigger day and LBRs, adjusting for covariates [relative risk (RR) 1.027, 95% confidence interval (CI) 1.007, 1.049]. Stratification analysis showed that the LBRs were positively associated (RR 1.052, 95% CI 1.004, 1.102) with every 1 ng/ml increase of serum E2 on the hCG trigger day for the subgroup with low antral follicle counts on the trigger day. Specifically, a two-piecewise linear regression model showed that there was a positive association (RR 1.188, 95% CI 1.057, 1.334) between serum E2 and LBR for every increase of 1 ng/ml E2 when the concentration of serum E2 was lower than 2.1 ng/ml. However, there was no significant association (RR 1.002, 95% CI 0.971, 1.032) between E2 levels and LBRs when the concentration of E2 was higher than the 2.1ng/ml inflection point.ConclusionsSerum E2 levels on the hCG trigger day were segmentally connected with LBRs.

show abstract

“…However, very few studies were included ( Kamath et al , 2017 ). More recently, a systematic review of the evidence for an adjuvant role of letrozole in IVF concluded that while anticipated poor responders may benefit from letrozole co-treatment, there remains insufficient evidence to support its use in normal and high responders ( Bülow et al , 2022a ).…”

Section: Introductionmentioning

confidence: 99%

Does adjuvant letrozole reduce uterine peristalsis prior to fresh embryo transfer?

Holt

Warzecha

Bülow

et al. 2022

Human Reproduction Open

Self Cite

View full text Add to dashboard Cite

STUDY QUESTION Does adjuvant letrozole in ovarian stimulation for in vitro fertilization (IVF) decrease the uterine peristalsis frequency (UPF) prior to fresh embryo transfer (ET)? SUMMARY ANSWER Adjuvant letrozole in ovarian stimulation for IVF does not reduce the UPF significantly prior to fresh ET. WHAT IS KNOWN ALREADY Throughout the cycle uterine peristalsis aids spermatozoa transport to the fallopian tube and may affect implantation. At fresh ET, UPF is negatively correlated with implantation and clinical pregnancy rates and is believed to be modulated by estradiol and progesterone. High levels of estradiol, from multiple follicular development, in ovarian stimulation have been reported to increase UPF, whereas progesterone is considered to be an utero-relaxant. The influence of androgens is unclear. Co-treatment with letrozole during gonadotropin ovarian stimulation limits the supra-physiological estradiol rise and may therefore reduce UPF prior to fresh ET. STUDY DESIGN, SIZE, DURATION This study was carried out on subjects participating in a single centre double blinded randomised controlled trial (RCT) of the impact of letrozole on follicle development and endocrine profiles, and investigated the impact of adjuvant letrozole in ovarian stimulation for IVF on UPF prior to fresh ET and the correlations of UPF with endocrine markers. Between 2016 and 2017, 39 women expected to be normal responders were randomised to co-treatment with letrozole or placebo. Of these, 33 women completed this element of the study. The study was carried out according to the Helsinki Declaration and the ICH-Good-Clinical-Practice. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible women were randomised 1:1 to adjuvant treatment with letrozole 5 mg/day or placebo in an antagonist protocol using a fixed dose of recombinant (r) FSH 150 IU/day. Final maturation was triggered with hCG 6,500 IU and luteal support with vaginal progesterone was administered from the day following oocyte aspiration. Less than one hour prior to fresh ET, six-minute duration transvaginal ultrasound recordings of the uterus in sagittal section were performed and blood samples were drawn. MAIN RESULTS AND THE ROLE OF CHANGE A total of 33 women completed the study (letrozole n = 17; placebo n = 16). Age, BMI and ovarian reserve markers were similar between the groups. On day of ET, serum estradiol levels were significantly suppressed in the letrozole group to a mean of 867 ± 827 pmol/L compared to 3,110 ± 1,528 pmol/L in the placebo group (P < 0.001). Mean UPF prior to fresh ET did not differ between the intervention and placebo group (3.3 ± 0.36 versus 3.5 ± 0.51 per minute respectively, P = 0.108). UPF was assessed and agreed by two observers who were blinded to adjuvant treatment. Two patients were excluded due to poor quality of the ultrasound recordings. Supra-physiological serum estradiol in the placebo group were negatively correlated with UPF (P = 0.014; R = -0.62), but the more physiological serum estradiol levels in the letrozole group showed no correlation with UPF (P = 0.567; R = 0.15). Serum progesterone levels were similar in both groups and did not show any significant correlation with UPF. Testosterone levels were significantly higher in the letrozole group (P = 0.005) and showed a non-significant trend that negatively correlated with UPF in the placebo group (P-value=0.071, R= -0.48). LIMITATIONS, REASONS FOR CAUTION Limitations of the study included the limited sample size and the lack of a power calculation specifically determined for this endpoint. WIDER IMPLICATIONS OF THE FINDINGS The supra-physiological levels of estradiol generated during ovarian stimulation were significantly suppressed in the intervention group. However, UPF prior to fresh ET was similar in both groups. Modulating the luteal phase sex steroids with adjuvant letrozole had little measured impact on UPF. Any beneficial effect of adjuvant letrozole during ovarian stimulation is unlikely to be due to significant modulation of UPF. STUDY FUNDING/COMPETING INTEREST(S) MDH's salary was funded by an unrestricted research grant from Gedeon Richter. The expenses of the study was funded by a scientific collaboration: ReproUnion, co-financed by the European Union, Interreg Öresund-Kattegat-Skagerrak and Ferring Pharmaceuticals. The assays for the analyses were funded by Roche Diagnostics and an unrestricted research grant from Merck Life Science AS, Denmark. The authors have no competing interests to declare regarding this study. TRIAL REGISTRATION NUMBER Clinicatrials.gov: NCT02939898, EudraCT no.: 2015-005683-41.

show abstract

Co-treatment with letrozole during ovarian stimulation for IVF/ICSI: a systematic review and meta-analysis

Abstract: Co-treatment with letrozole during ovarian stimulation for IVF/ICSI -a systematic review and metaanalysis, Reproductive BioMedicine Online (2021), doi:

Cited by 16 publications

References 71 publications

Letrozole cotreatment with progestin-primed ovarian stimulation in women with polycystic ovary syndrome undergoing IVF treatment

Letrozole cotreatment with progestin-primed ovarian stimulation in women with polycystic ovary syndrome undergoing IVF treatment

The Association Between Serum Estradiol Levels on hCG Trigger Day and Live Birth Rates in Non-PCOS Patients: A Retrospective Cohort Study

Does adjuvant letrozole reduce uterine peristalsis prior to fresh embryo transfer?

Contact Info

Product

Resources

About