Effect Sildenafil and Estradiiol Valerate on Endometrial Thickness in Infertile Women

The Effect of Estradiol Valerate With and Without Oral Sildenafil on Endometrial Thickness and Pregnancy Rates in Infertile Women: A R.C.T

The endometrium is a dynamic tissue that responds to changing hormonal signals throughout the cycle. The changes in the endometrial composition are expressed in alteration in gene expression, micro architectural morphological changes as well as in protein and hormone secretion. These factors combine together to construct the "window of implantation" a short period of time during the luteal phase in which the endometrium is receptive.

Thin endometrium is associated with a low pregnancy rate. Endometrial thickness 7 mm in the pre-ovulatory phase is widely accepted to be cut-off of thin endometrium.

for that the aim of this study is to compare the effect of sildenafil-estrogen combination to estrogen alone on endometrium thickness in infertile women. Half of the patients will receive estrogen ( estradiol valerate ) and the other half will receive combination of sildenafil-estrogen .

Study Overview

• Status: Completed
• Conditions: Endometrial Thickness
• Intervention / Treatment: Drug: estradiol valerate and sildenafil

Detailed Description

Being a hormone dependent tissue, the endometrium proliferates in response to estrogen, which further induces the production of progesterone receptors. As a result, infertile patients who demonstrated thin endometrium, were offered estradiol (E2) remedies, in an attempt to improve endometrial proliferation. Most of the studies regarding E2 treatment in patients with thin endometrium dealt with frozen-thawed embryo transfer cycles. Moreover, while there are several routes and duration of administration of E2, including per Os, transdermal, Intramuscular and vaginal, no compelling advantage for one protocol for endometrial preparation over another, with regard to pregnancy rates, has been established.

Sildenafil acts as a type 5-specific phosphodiesterase inhibitor hence augments the vasodilatory effects of nitric oxide by preventing the degradation of cGMP. Nitric oxide (NO) relaxes vascular smooth muscle through a cGMP-mediated pathway and NO synthase isoforms have been identified in the uterus. A decade ago, Sher and Fisch studied the effect of vaginal sildenafil on the endometrial thickness of infertile patients with poor endometrial development, who underwent IVF treatment. They have demonstrated improved uterine artery blood flow and endometrial growth, with higher implantation and ongoing pregnancy rates following vaginal sildenafil administration.

• Study Type: Interventional
• Enrollment (Actual): 90
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Egypt
  • Cairo, Egypt
    • Ain Shams University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 33 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Patients having ovulatory infertility.
2. Age: 20-35 years old.
3. BMI less than 30 kg/m2

Exclusion Criteria:

1. Women who have any congenital uterine anomaly (e.g., unicornuate uterus or infantile uterus) or acquired deformities of the uterine cavity that interfere with embryo implantation (as Asherman Syndrome).
2. Women who have any tubal factor that relates to infertility (e.g., tubal adhesion or previous ectopic pregnancy).
3. Women who have contraindication for estrogen treatment (e.g., history of stroke, DVT and Benign liver disease).
4. Women who have male factor for infertility (e.g., azoospermia, teratospermia).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: estradiol valerate; oral estradiol valerate (Cyclo-Progynova ® 2mg, white tablets, BAYER Schering Pharma). One tablet every 12 hour from 2nd day of the cycle till the day of trigger of ovulation).	Drug: estradiol valerate and sildenafil; (45 women will receive clomiphene citrate (clomid 50mg ®, Sanofi aventis) 2 tab. single dose orally from the 2nd day of the cycle for 5 days with oral estradiol valerate (Cyclo-Progynova ® 2mg, white tablets, BAYER Schering Pharma), one tablet every 12 hour from 2nd day of the cycle + sildenafil (silden® 25, E.I.P.I.CO.) every 8 hour from 2nd day of the cycle till the day of trigger of ovulation).; Other Names: cycloprogenova and silden
Experimental: estradiol valerate and sildenafil; oral estradiol valerate (Cyclo-Progynova ® 2mg, white tablets, BAYER Schering Pharma), one tablet every 12 hour from 2nd day of the cycle + sildenafil (silden® 25 mg, E.I.P.I.CO.) every 8 hour from 2nd day of the cycle till the day of trigger of ovulation).	Drug: estradiol valerate and sildenafil; (45 women will receive clomiphene citrate (clomid 50mg ®, Sanofi aventis) 2 tab. single dose orally from the 2nd day of the cycle for 5 days with oral estradiol valerate (Cyclo-Progynova ® 2mg, white tablets, BAYER Schering Pharma), one tablet every 12 hour from 2nd day of the cycle + sildenafil (silden® 25, E.I.P.I.CO.) every 8 hour from 2nd day of the cycle till the day of trigger of ovulation).; Other Names: cycloprogenova and silden

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
endometrial line thickness	The thickness of the endometrium will be measured (maximum distance between each myometrial/endometrial interface through the longitudinal axis of the uterus) using two dimensional transvaginal ultrasound.	9 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
positive pregnancy test	Serum B-HCG	14 days after triggering of ovulation
sub endometrial blood flow	Using two dimensional (2D) transvaginal Doppler, flow velocity wave forms will be obtained from the ascending main branch of the uterine artery on the right and left side of the cervix before it enters the uterus.	9 days

Collaborators and Investigators

• Sponsor: Ain Shams University

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2017
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): July 30, 2018

Study Registration Dates

• First Submitted: September 24, 2017
• First Submitted That Met QC Criteria: September 28, 2017
• First Posted (Actual): October 4, 2017

Study Record Updates

• Last Update Posted (Actual): August 14, 2018
• Last Update Submitted That Met QC Criteria: August 13, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infertility; 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: 2

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