This study adds letrozole to hormonal therapy before frozen embryo transfer (FET).

Study Background

WHAT

• Does adding letrozole for five days onto estrogen-progesterone protocols for FET improve rates of pregnancy?

WHY

• Increasing studies show that letrozole can benefit embryo implantation

• Lack of research adding letrozole to hormone treatment shortly before embryo implantation = interest in impact on ongoing rate of pregnancy

WHERE

• Obstetrics and Gynecology Department, Zagazig University, Cairo, Egypt

WHEN

• August 2020- February 2021

WHO

• Women ages 18-37

• One good-quality blastocyst (day 5) available for transfer

• Endometrial lining at least 9 mm after supplemental estrogen

HOW

• Oral estradiol valerate (2 mg three times daily) started on Day 2 or 3 targeting endometrial thickness of 9 mm or greater

• Once desired thickness reached, randomization by sealed envelope method* in 1:1 ratio into two groups

  • Letrozole Group = added on five days of oral letrozole (2.5 mg twice daily) to oral estrogen before starting intramuscular progesterone in oil (100 mg daily)

  • Control Group = oral estrogen, no letrozole, then addition of intramuscular progesterone

    *Uninvolved assistant determined randomization, patient selected envelope

• Frozen embryos warmed and transferred on progesterone day 6

• Post-embryo transfer, added daily progesterone (100 mg intramuscular once daily + oral 100 mg three times daily) and continued estradiol

• If clinically pregnant, started vaginal progesterone at 100 mg three times daily, continued oral estrogen and progesterone, and decreased intramuscular progesterone to every third day.

• Stopped supplemental estrogen and progesterone at 10 and 12 weeks gestation, respectively

• Ongoing pregnancy: fetal cardiac pulsation at 12+ weeks gestation

Statistics (for the Uber Curious)

Sample size N= 56 women per group calculated from:

• Needed 54 women per group for Chi-square test for independent samples; alpha error 0.05, power of 80%

• Pilot study of 25 women showing ongoing pregnancy of 80% (letrozole) vs. 55% (control)

• expected cancellation of embryo transfer of 4%

Results

• 55 women analyzed in Letrozole Group; 54 women analyzed in Control Group

• Ongoing pregnancy rates higher in Letrozole Group vs. Control Group (RR 1.39, 95% CI 1.04-1.86, p =0.023)

• Clinical pregnancy rates higher in Letrozole Group vs. Control Group (RR 1.31, 95% CI 1.02-1.68, p =0.03)

• No statistical significance between groups for endometrial compaction (p =. 0.776)

• Estradiol levels in N = 40 of Letrozole Group:

  • 26.6% decline from reaching target endometrial thickness on estrogen and finishing letrozole (p < 0.001)

  • 12.6% increase on day of FET (p =0.015)

  • 16% median decline from reaching target endometrial thickness to day of FET ( (p < 0.001)

Authors’ Thoughts

• Study limitations: no placebo, no data on live births, results limited to inclusion criteria

• Letrozole: used here to decrease estradiol and increase implantation

  • Drug may accrue within endometrium, lasting beyond half-life of ~48hr; mechanism of action is presently unknown

  • First known study of this drug used, not with gonadotropins, but after / during estrogen prep and before starting progesterone

• Supplementary estradiol and progesterone (HRT) based on prior research + unit protocol

• Endometrium

  • Necessary to have adequate estradiol priming to proliferate endometrium and induce progesterone receptors - selected target of 9 mm endometrial thickness to maximize outcomes

  • Ongoing and clinical pregnancy not affected by state of endometrial compaction (and compaction not impacted by estradiol)

This Pharmacist’s Thoughts

(+) carefully researched prior to manuscript publication, adequately powered, letrozole is cheap and convenient to take (feasible add-on for most women doing embryo transfer)

(-) unblinded, study did not disclose all methodology involving sealed envelope randomization - were additional security measures used?

Conclusions

This study offers an exciting first look at a new role for letrozole in helping women to conceive. Clearly, more studies are needed that are blinded, record live birth rates, and test alternate dosing regimens of estradiol and progesterone.

Resources

Bülow NS, Dreyer Holt M, Skouby SO, et al. Co-treatment with letrozole during ovarian stimulation for IVF/ICSI: a systematic review and meta-analysis [published online ahead of print, 2021 Dec 22]. Reprod Biomed Online. 2021;S1472-6483(21)00604-0. doi:10.1016/j.rbmo.2021.12.006

Comhaire F, Decleer W. Comparing the effectiveness of infertility treatments by numbers needed to treat (NNT). Andrologia. 2012;44(6):401-404. doi:10.1111/j.1439-0272.2012.01295.x

Elgindy EA, Abdelghany AA, Sibai AbdAlsalam H, Mostafa MI. The novel incorporation of aromatase inhibitor in hormonal replacement therapy cycles: a randomized controlled trial [published online ahead of print, 2021 Dec 20]. Reprod Biomed Online. 2021;S1472-6483(21)00611-8. doi:10.1016/j.rbmo.2021.10.025

Hart RJ. Stimulation for low responder patients: adjuvants during stimulation. Fertil Steril. 2022;117(4):669-674. doi:10.1016/j.fertnstert.2022.01.027

Moini A, Lavasani Z, Kashani L, Mojtahedi MF, Yamini N. Letrozole as co-treatment agent in ovarian stimulation antagonist protocol in poor responders: A double-blind randomized clinical trial. Int J Reprod Biomed. 2019;17(9):653-660. Published 2019 Sep 22. doi:10.18502/ijrm.v17i9.5101

Torgerson DJ, Roberts C. Understanding controlled trials. Randomisation methods: concealment. BMJ. 1999;319(7206):375-376. doi:10.1136/bmj.319.7206.375

Yang AM, Cui N, Sun YF, Hao GM. Letrozole for Female Infertility. Front Endocrinol (Lausanne). 2021;12:676133. Published 2021 Jun 16. doi:10.3389/fendo.2021.676133