Endometrial Effects of Sildenafil in Frozen-Thawed Cycles in Women With Thin Endometrium

Effect of Sildenafil on Uterine and Endometrial Vasculature in Women With Thin Endometrium Having Frozen-Thawed IVF Cycles

Management of Thin endometrium in IVF is challenging. Thin endometrium is often defined as <7 mm or < 8 mm on the day of Human Gonadotropin administration(Bu and Sun, 2015; Wu et al., 2014).

Its incidence is 1-2.5% in most studies ( AlGhamdi et al.,2008).

Endometrial thickness and endometrial vascularity is closely linked to endometrial receptivity.Improving endometrial receptivity is a predictor of the success in IVF.

Many medications have been tried to improve endometrial thickness as Aspirin,sildenafil citrate,luteal estradiol and Granulocyte colony stimulating factor.

Nitric oxide (NO) is a key signaling molecule involved in the vasodilator response of smooth muscle cells. NO activates the cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway within smooth muscle cells to promote smooth muscle cell relaxation. Sildenafil citrate inhibits phosphodiesterase 5 (PDE5) maintaining activation of cGMP and PKG and maximizing the effect of existing NO, thus facilitating smooth muscle cell relaxation. The potent vasodilator action of sildenafil has led researchers to evaluate sildenafil as a treatment in assisted reproduction where low uterine blood flow is perceived to be a contributor to implantation failure (Fairouzabadi et al.2013).

The investigators aim at this study to investigate the role of sildenafil citrate on endometrial and subendometrial vasculature in women with thin endometrium undergoing Frozen-Thawed IVF cycles.

Study Overview

• Status: Not yet recruiting
• Conditions: IVF; Endometrial Receptivity
• Intervention / Treatment: Other: Placebo; Drug: Estradiol Valerate; Drug: Sildenafil Citrate

Detailed Description

This is a Randomised-controlled trial .The investigators recruited 100 women who are known to have thin endometrium in previous IVF cycles (failed/cancelled cycles).

They are randomised into group A (50 women) : preparation of the endometrium with Estradiol valerate 2mg/day (every 8 hours)(white tablets of cycloprogenova,Payer,Germany) from the first day of the cycle till 12th day and The investigators add placebo from the first day of the cycle till the day of starting progesterone (It will be stopped 3 days before embryo transfer).Group B (50 women): The investigators add Sildenafil citrate (Viagra,pfizer,United states) to the estradiol valerate. Sildenafil 50 mg will be used daily from the first day of the cycle till the day of starting progesterone (It will be stopped 3 days before embryo transfer). The embryos will be transferred depending on their age on day 3 or day 5.

At the transfer date ,the investigators will assess the endometrial thickness, endometrial volume, uterine artery doppler indices (RI,PI) as well as 3D endometrial vascular indices (VI,FI,VFI) .

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Eman Elkattan, MD; Phone Number: 01212529213; Email: emyelkattan@gmail.com
• Study Contact Backup: Name: wafaa Ramadan, MD; Phone Number: 01019944328

Study Locations

• Egypt
  • Cairo, Egypt
    • Cairo University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 40 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Women (25 -40 years) undergoing IVF frozen-Thawed cycles and known to have good quality embryos.
• previous thin endometrium (< 8mm on at least 3 previous cycles) with normal Hysteroscopy findings

Exclusion Criteria:

• women less than 25 years old or more than 40 years old.
• abnormal hysteroscopic findings.
• women with congenital uterine anomalies.
• History of previous uterine surgery
• Any contraindication to Sildenafil as Previous history of cardiac disease or stroke.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: estradiol valerate + placebo; preparation of the endometrium with Estradiol valerate 2mg/day (every 8 hours)(white tablets of cycloprogenova) .from the first day of the cycle till 12th day and we add placebo from the first day of the cycle till the day of start progesterone (we stop 3 days before embryo transfer).	Other: Placebo; Placebo tablet (multivitamins),Pregnacare vitamins (Vitabiotics,UK); Other Names: Pregnacare vitamins (Vitabiotics,UK); Drug: Estradiol Valerate; Estradiol valerate tablets 2mg every 8 hours daily starting from the fist day of the cycle till 12th day of the menstrual cycle.
Experimental: estradiol valerate + Sildenafil citrate; We add Sildenfil citrate 50 mg daily from the first day of the period till the day of starting the progesterone. and stop 3 days before the embryo transfer.	Drug: Estradiol Valerate; Estradiol valerate tablets 2mg every 8 hours daily starting from the fist day of the cycle till 12th day of the menstrual cycle.; Drug: Sildenafil Citrate; Sildenafil Citrate 50 mg tablets taken from the first day of the cycle till the day we start progesterone (we stop 3 days before embryo transfer)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Clinical Pregnancy rate	2 weeks after embryo transfer

Secondary Outcome Measures

Outcome Measure	Time Frame
endometrial thickness	at the time of embryo transfer
Endometrial volume	at the time of embryo transfer
Uterine artery doppler indices	at the time of embryo transfer
3D endometrial and subendometrial vascular indices(VI,FI.VFI)	at the time of embryo transfer

Collaborators and Investigators

• Sponsor: Cairo University

Study record dates

Study Major Dates

• Study Start (Anticipated): September 1, 2021
• Primary Completion (Anticipated): March 1, 2022
• Study Completion (Anticipated): March 1, 2022

Study Registration Dates

• First Submitted: February 18, 2020
• First Submitted That Met QC Criteria: February 21, 2020
• First Posted (Actual): February 25, 2020

Study Record Updates

• Last Update Posted (Actual): August 20, 2021
• Last Update Submitted That Met QC Criteria: August 14, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Estradiol; Sildenafil Citrate; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Polyestradiol phosphate
• Other Study ID Numbers: PROTOCOL 500

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No