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

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