Taking Tadalafil to Improve Embryo Implantation

This is the first study to test the use of vaginal tadalafil on endometrial thickness and pregnancies in women using IVF to conceive.

Study Background

WHAT

• Does tadalafil build the uterine lining better than placebo?

• Does vaginal tadalafil provide better results than oral tadalafil?

WHY

• Endometrial thickness influences embryo implantation

• PDE-5 inhibitors influence endometrium development

• Tadalafil has longer half-life (17.5 hours) vs. sildenafil (~4 hours)

WHERE

• One hospital site in Ghent, Belgium

WHEN

• March - September 2019

WHO

• 58 women struggling to conceive

  • ages 18-40 years

  • attempting IVF for the first, second, or third time (any indication for IVF)

• Excluded women with BMI > 35 kg/m2, abnormal uterine cavity, known major organ disease, history of myocardial infarction or vascular disease, or a contraindication for tadalafil

HOW

• Randomized, double-blind, placebo-controlled prospective trial

  • Double-blind: blinding not elucidated

  • Randomized 1:1:1 via computer program

• Treatments by Group:

  • Group A: oral tadalafil + vaginal placebo

  • Group B: oral placebo + vaginal tadalafil

  • Group C: oral placebo + vaginal placebo

• Vaginal tadalafil compounded by local pharmacist from oral tadalafil capsules

• Patients completed study protocol as shown in figure below

• 1-2 embryos transferred after 3 or 5 days of fertilization; received endometrial support as micronized vaginal progesterone caps

Figure from study BALDUYCK et al.

rFSH = recombinant follicular stimulating hormone, GnRH= gonadotropin-releasing hormone, hCG = human chorionic gonadotrophin (ovulation trigger), OR = oocyte retrieval, ET= embryo transfer.

Statistics

• Baseline characteristics between groups: student t-test (n < 30)

• Endometrial thickness and pregnancy: one-way analysis of variance (ANOVA)

  Results

• 58/58 patients completed study (zero dropouts/lost to follow-up)

• Patient characteristics similar between groups (BMI, age, FSH, rFSH dosing)

• Endometrial thickness showed no statistically significant differences between groups

• Group B had more cumulative oocyte complexes (COCs) and mature oocytes (MIIs) vs. Groups A and C ; statistically significant at p = 0.017 and p = 0.043 respectively

• No statistically significant differences in 2PN zygotes and cryopreserved embryos, but higher # embryos in Groups A & B vs. Group C

• Trend towards more biochemical and clinical pregnancies in Group A vs. Groups B & C but no statistically significant differences

  Authors’ Conclusions

• No mean differences in endometrial thickness or pregnancies between groups

• Future studies should consider:

  • recruiting more patients

  • selecting patients based on thin endometrium in past IVF cycles

  • assessing live-birth rates as an outcome

• Not possible to draw conclusion on role of vasodilators in fertility treatment

  
  This Pharmacist’s Conclusions

  (+) randomization (with sufficient explanation); all patients allocated to intervention remained in the trial; stopped tadalafil prior to ovulation to ensure embryo safety

  (-) scant explanation for why results did not confirm hypotheses; poor explanation of formulation for vaginal application; under-explained the dosing selection for 10 mg tadalafil; lack of smoker status in baseline demographics (12% of Belgian women are smokers and cigarette use is linked to endometrial thickness)

This pilot study demonstrated a potential for differences in pregnancy outcomes using tadalafil vs. placebo, but larger, potentially dose-ranging studies are needed before routinely incorporating oral or vaginal tadalafil into IVF protocols.

Resources

Balduyck J, Ameye A, Decleer W. Effect of vaginal/oral tadalafil on endometrial thickness in IVF patients: a double-blind, placebo controlled RCT: a pilot study. Facts Views Vis Obgyn. 2022;14(2):155-161. doi:10.52054/FVVO.14.2.026

Belapurkar P, Jaiswal A, Madaan S. Comparison of Efficacy Between Vaginal Sildenafil and Granulocyte-Colony Stimulating Factor (G-CSF) in Improving Endometrial Thickness (ET) in Infertile Women. Cureus. 2022;14(6):e26415. Published 2022 Jun 29. doi:10.7759/cureus.26415

Cialis. Package Insert. Eli Lilly and Company; 2011.

Heger A, Sator M, Walch K, Pietrowski D. Smoking Decreases Endometrial Thickness in IVF/ICSI Patients. Geburtshilfe Frauenheilkd. 2018;78(1):78-82. doi:10.1055/s-0043-123762

Mostafa T. Useful Implications of Low-dose Long-term Use of PDE-5 Inhibitors. Sex Med Rev. 2016;4(3):270-284. doi:10.1016/j.sxmr.2015.12.005