STUDY QUESTION Does letrozole co-treatment during ovarian stimulation with gonadotrophins for IVF reduce the proportion of women with premature progesterone levels above 1.5 ng/ml at the time of triggering final oocyte maturation? SUMMARY ANSWER The proportion of women with premature progesterone above 1.5 ng/ml was not significantly affected by letrozole co-treatment. WHAT IS KNOWN ALREADY IVF creates multiple follicles with supraphysiological levels of sex steroids interrupting the endocrine milieu and affects the window of implantation. Letrozole is an effective aromatase inhibitor, normalizing serum oestradiol, thereby ameliorating some of the detrimental effects of IVF treatment. STUDY DESIGN, SIZE, DURATION A randomized, double-blinded placebo-controlled trial investigated letrozole intervention during stimulation for IVF with FSH. The trial was conducted at four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS A cohort of 129 women with expected normal ovarian reserve (anti-Müllerian hormone 8–32 nmol/l) completed an IVF cycle with fresh embryo transfer and received co-treatment with either 5 mg/day letrozole (n = 67) or placebo (n = 62), along with the FSH. Progesterone, oestradiol, FSH, LH and androgens were analysed in repeated serum samples collected from the start of the stimulation to the mid-luteal phase. In addition, the effect of letrozole on reproductive outcomes, total FSH consumption and adverse events were assessed. MAIN RESULTS AND THE ROLE OF CHANCE The proportion of women with premature progesterone >1.5 ng/ml was similar (6% vs 0% (OR 0.0, 95% CI [0.0; 1.6], P = 0.12) in the letrozole versus placebo groups, respectively), whereas the proportion of women with mid-luteal progesterone >30 ng/ml was significantly increased in the letrozole group: (59% vs 31% (OR 3.3, 95% CI [1.4; 7.1], P = 0.005)). Letrozole versus placebo decreased oestradiol levels on the ovulation trigger day by 68% (95% CI [60%; 75%], P < 0.0001). Other hormonal profiles, measured as AUC, showed the following results. The increase in LH in the letrozole group versus placebo group was 38% (95% CI [21%; 58%], P < 0.0001) and 34% (95% CI [11%; 61%], P = 0.006) in the follicular and luteal phases, respectively. In the letrozole group versus placebo group, testosterone increased by 79% (95% CI [55%; 105%], P < 0.0001) and 49% (95% CI [30%; 72%], P < 0.0001) in the follicular and luteal phases, respectively. In the letrozole group versus placebo group, the increase in androstenedione was by 85% (95% CI [59%; 114%], P < 0.0001) and 69% (95% CI [48%; 94%], P < 0.0001) in the follicular and luteal phases, respectively. The ongoing pregnancy rate was similar between the letrozole and placebo groups (31% vs 39% (risk-difference of 8%, 95% CI [−25%; 11%], P = 0.55)). No serious adverse reactions were recorded in either group. The total duration of exogenous FSH stimulation was 1 day shorter in the intervention group, significantly reducing total FSH consumption (mean difference −100 IU, 95% CI [−192; −21], P = 0.03). LIMITATIONS, REASONS FOR CAUTION Late follicular progesterone samples were collected on the day before and day of ovulation triggering for patient logistic considerations, and the recently emerged knowledge about diurnal variation of progesterone was not taken into account. The study was powered to detect hormonal variations but not differences in pregnancy outcomes. WIDER IMPLICATIONS OF THE FINDINGS Although the use of letrozole has no effect on the primary outcome, the number of women with a premature increase in progesterone on the day of ovulation triggering, the increased progesterone in the mid-luteal phase due to letrozole may contribute to optimizing the luteal phase endocrinology. The effect of letrozole on increasing androgens and reducing FSH consumption may be used in poor responders. However, the effect of letrozole on implantation and ongoing pregnancy rates should be evaluated in a meta-analysis or larger randomized controlled trial (RCT). STUDY FUNDING/COMPETING INTEREST(S) Funding was received from EU Interreg for ReproUnion and Ferring Pharmaceuticals, and Roche Diagnostics contributed with assays. N.S.M. and A.P. have received grants from Ferring, Merck Serono, Anecova and Gedeon Richter, and/or personal fees from IBSA, Vivoplex, ArtPred and SPD, outside the submitted work. The remaining authors have no competing interests. TRIAL REGISTRATION NUMBERS NCT02939898 and NCT02946684 TRIAL REGISTRATION DATE 15 August 2016. DATE OF FIRST PATIENT’S ENROLMENT 22 August 2016.
Co-treatment with letrozole during ovarian stimulation for IVF/ICSI -a systematic review and metaanalysis, Reproductive BioMedicine Online (2021), doi:
Androgen priming has a biological basis for improving poor response during ovarian stimulation. While administration of exogenous androgens may have effects on early stages of follicle development, they are unlikely to affect the androgen concentrations in more mature follicles. Conversely, administration of hormones that increases the intra-follicular androgen concentration may have effects across a broader range of stage of follicle development.
Study question Does letrozole co-treatment during ovarian stimulation for in vitro fertilization (IVF) impact oocyte yield, embryo development, and live birth rate (LBR) in expected normal responders? Summary answer Letrozole co-treatment leads to similar oocyte yield, embryo- development and utilisation rate, and live birth rate after transfer in the fresh cycle. What is known already Letrozole reduces oestradiol levels by inhibiting the aromatization of androgens, this diminishes pituitary suppression and increases endogenous gonadotrophin release. These effects are utilized in ovulation induction in PCOS patients and may benefit certain patients during IVF treatment. In addition, we have recently reported in an RCT that co-treatment with letrozole increases luteal phase progesterone levels and, consistent with previous studies, no significant effect on pregnancy rates was observed. However, the impact of the changes in the endocrine milieu caused by letrozole co-treatment on the developing oocytes and embryos remains unclear as most published studies are retrospective and lack appropriate control-groups. Study design, size, duration A multicentre double-blinded randomised placebo-controlled trial was conducted in four fertility clinics at University Hospitals in Denmark from August 2016 to November 2018. 159 women were randomised, 129 women received single embryo (cleavage stage or blastocyst) transfer in the fresh cycle, and the surplus 257 embryos were vitrified. The study was conducted following the Helsinki Declaration and the ICH-Good-Clinical-Practice. Data collection and reporting followed the guidelines of CONSORT to achieve transparent reporting of trials. Participants/materials, setting, methods Women with expected normal ovarian response received an antagonist protocol with fixed-dose FSH. Co-treatment consisted of 5mg letrozole or placebo from the start of stimulation until the day of triggering final oocyte maturation with hCG. Standardized morphological evaluation was performed at all centres (applying the Istanbul consensus and Gardner-score). A sub-cohort of the embryos were cultured in an EmbryoScope incubator and further assessed by morphokinetic annotation and reported with.KIDScoreD3. Ongoing pregnancies were followed until birth. Main results and the role of chance A total of 1268 oocytes were retrieved from 154 women, leading to development of 386 usable embryos that were either transferred or vitrified. Utilisation rate (the proportion of usable embryos to oocytes) was similar in the letrozole group and placebo group with 0.31 vs. 0.36 (mean difference (MD): -0.05, 95% CI[-0.03;0.12], P = 0.25). Morphologically grading the embryos as “good”, “fair”, and “poor” quality showed similar results, the odds of having a higher quality were 0.78 times higher in the letrozole- vs. placebo group (CI[0.5;1.1], P = 0.2). Morphokinetic annotations (n = 302 embryos) showed similar results with the odds of having a high KIDScore3 1.3 times higher in the letrozole – vs. placebo group (CI[0.9;2.1], P = 0.2). The endometrial thickness at transfer was thinner in the letrozole compared to the placebo group with 8.5 vs. 9.5 mm (MD 1.0, 95% CI[0.4;1.6], P = 0.001) but with the same ultrasonic echogenicity and a preovulatory three-layer appearance. After embryo transfer in the fresh cycle (n = 129), no differences were seen in the pregnancy outcomes: positive serum hCG, ongoing pregnancy rate, early miscarriage rate, foetal miscarriage rate, or LBR. LBR per initiated cycle were similar as well (n = 159): 23.8% vs. 29.1% (MD of -5,3%, CI[-20.3%;9.6%], P = 0.48) in letrozole vs. placebo group, respectively. Limitations, reasons for caution Four clinics participating could lead to interobserver variability. However, bias was reduced by block-randomised design. All data are derived from an RCT, the primary endpoint of which, preovulatory progesterone, was the basis of the sample size calculation. The study may have been underpowered to show a significant impact on LBR. Wider implications of the findings Letrozole co-treatment during ovarian stimulation with gonadotrophins did not have an impact on the oocyte yield and embryo development. These data suggest that letrozole co-treatment is unlikely to compromise outcomes in its growing indications: ovulation induction, IVF in poor responders, and fertility preservation in breast cancer patients. Trial registration number NCT02946684
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.
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