Impact of letrozole co-treatment during ovarian stimulation with gonadotrophins for IVF: a multicentre, randomized, double-blinded placebo-controlled trial

Abstract

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.

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

“…The mean serum progesterone level showed a trend towards a higher level in the letrozole group, which may reflect greater endogenous production secondary to reduced oestradiol suppression of LH ( Bülow et al , 2022b ). The majority of patients in both groups had the ET 3 days after oocyte aspiration, which meant that they had been exposed to vaginal progesterone for 2 days when blood were drawn.…”

“…The high serum oestradiol levels that arise at the folliculo-luteal phase transition as a consequence of ovarian stimulation act to suppress pituitary gonadotropin secretion, necessitating luteal phase support. The use of adjuvant letrozole, an aromatase inhibitor, during ovarian stimulation, limits the supraphysiological rise in oestradiol normally observed, leading to a higher endogenous gonadotropin secretion in the luteal phase ( Bülow et al , 2022b ). This may increase serum progesterone levels in the luteal phase.…”

Letrozole Supplementation and the Increased Risk of Elevated Progesterone Levels on Trigger Day

“…Our research indicates that LE poses a strong risk of increasing progesterone levels. Regarding the mechanism through which LE elevates progesterone, we hypothesised LE inhibited the production of oestrogen (mainly oestradiol), resulting in the accumulation of oestrogen synthesis precursors and androgens (e.g., testosterone and androstenedione) ( 14 ). Once the accumulation of androgens reaches a certain threshold, progesterone accumulates, increasing its levels in the blood, which has also been proven in previous studies ( 14 , 19 ).…”

“…Letrozole competitively binds to the heme group of the cytochrome P450 subunit of aromatase, blocking the conversion of androstenedione and testosterone to oestrone and oestradiol, leading to an increase in androgen and a decrease in oestrogen levels ( 14 ). Therefore, LE is commonly used to promote ovulation under conditions of low ovarian reserve to increase the ovarian response to FSH ( 1 , 12 ).…”

“…In some randomised controlled trials (RCT), LE use in normal responders did not significantly up-regulate progesterone on trigger day ( 17 , 18 ). Other RCTs showed that LE supplementation increases the incidence of premature progesterone rise in the late follicular phase of IVF/ICSI ( 19 ) or increases progesterone levels ( 14 , 20 ). Reports on the effects of LE on progesterone levels during ovulation induction are inconsistent, largely because the above findings are based on RCTs with small sample sizes.…”