The Outcomes of ICSI Cycles With and Without Letrozole

Phase 4

• Conditions: EMBRYO IMPLANTATION
• Interventions: Drug: Letrozole 2.5Mg Tablet; Drug: Gonadotropins; Procedure: endometrial sample in the pretreatment cycle

• Registration Number: NCT04159649
• Lead Sponsor: Mansoura University

Brief Summary

A variety of genes working together with ovarian hormones conducts and precisely control the process of endometrial receptivity and implantation.

Leukemia inhibitory factor and αvβ3 integrin are two markers of implantation with at most importance. Reports have emphasized that these important biomarkers have a great role during the process of embryonic implantation.

αvβ3 integrin is one of the adhesion molecules which has a critical role in blastocyst apposition and attachment. Many studies have demonstrated that abnormal expression of αvβ3 integrin is associated with poor reproductive outcomes. Other studies haven't found a strong relation between αvβ3 integrin expression and reproductive outcomes Letrozole is an aromatase inhibitor which has been used in controlled ovarian stimulation especially in women with PCOS . Data suggests that letrozole addition to gonadotropins during ovarian stimulation protocols improve the response of the ovaries to FSH in low responders and increase the number of preovulatory follicles without adversely affect the outcomes.

Letrozole is used as an adjuvant therapy in ovarian stimulation protocols. So this study aims to evaluate whether the use of letrozole in combination with gonadotropins and GnRH antagonist is superior to gonadotropins and antagonist alone in women undergoing ICSI treatment.

Furthermore, both αvβ3 integrin and leukemia inhibitory factor are important markers of endometrial receptivity and implantation. Therefore, this study aims to assess the correlation between mid-luteal gene expression of both αvβ3 integrin and leukemia inhibitory factor and the clinical outcomes of antagonist cycles with or without letrozole.

Detailed Description

Embryo implantation depends on quality of the embryo, endometrial receptivity and embryo/endometrial interaction. It is estimated that two third of implantation failure is a result of defects in endometrial receptivity. A variety of genes working together with ovarian hormones conducts and precisely control the process of endometrial receptivity and implantation.

Leukemia inhibitory factor and αvβ3 integrin are two markers of implantation with at most importance. Reports have emphasized that these important bio-markers have a great role during the process of embryonic implantation . Both are expressed in the epithelial cells during the mid-secretory phase of the menstrual cycle in healthy fertile women and their absence is associated with infertility and recurrent pregnancy loss .

Leukemia inhibitory factor is a class of cytokines which plays a key role in the process of implantation in both human and animals . Studies suggest that absence of leukemia inhibitory factor in the endometrium has a negative impact on embryo implantation .

αvβ3 integrin is one of the adhesion molecules which has a critical role in blastocyst apposition and attachment. Many studies have demonstrated that abnormal expression of αvβ3 integrin is associated with poor reproductive outcomes . Other studies haven't found a strong relation between αvβ3 integrin expression and reproductive outcomes.

Letrozole is an aromatase inhibitor which has been used in controlled ovarian stimulation especially in women with PCOS . Data suggests that letrozole addition to gonadotropins during ovarian stimulation protocols improve the response of the ovaries to FSH in low responders and increase the number of preovulatory follicles without adversely affect the outcomes.

The study by Miller and his colleagues suggested that letrozole might improve αvβ3 integrin expression with possible increase in pregnancy and implantation rate. They suggested that, this drug may be a useful adjunct therapy during IVF protocols .

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2019-07-15
• Status Verified: 2019-11
• Study First Submitted QC: 2019-11-08
• Study First Posted: 2019-11-12
• Study Start: 2019-12-01
• Last Update Submitted: 2019-12-13
• Last Update Posted: 2019-12-16
• Primary Completion: 2020-12-30
• Study Completion: 2020-12-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: Female
• Target Recruitment: 224

Inclusion Criteria

Women aged from 18 - 40 years old.

• Regular menstrual cycle (25-35).
• Women undergoing ICSI cycle

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Exclusion Criteria

Women younger than 18 or older than 40 years old.

• Women who had unilateral oophorectomy.
• Women who had uterine abnormality or pathology.
• Women who will not meet the inclusion criteria.
• Women who will refuse to participate in in the study.
• ICSI cycles with fresh or frozen TESE samples.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
letrozole, gonadotropins and fixed GnRH antagonist	Letrozole 2.5Mg Tablet	letrozole (2.5 mg) will be given from the second day of the cycle and for 5 days, gonadotropins will be given from the third day of the cycle and GnRH antagonist will be added from the six day of the cycle for controlled ovarian stimulation in IVF (interventional group). Participant will be exposed to mid luteal endometrial sample in the pretreatment cycle. couples will be asked to use condom in the pretreatment cycle.
letrozole, gonadotropins and fixed GnRH antagonist	Gonadotropins	letrozole (2.5 mg) will be given from the second day of the cycle and for 5 days, gonadotropins will be given from the third day of the cycle and GnRH antagonist will be added from the six day of the cycle for controlled ovarian stimulation in IVF (interventional group). Participant will be exposed to mid luteal endometrial sample in the pretreatment cycle. couples will be asked to use condom in the pretreatment cycle.
letrozole, gonadotropins and fixed GnRH antagonist	endometrial sample in the pretreatment cycle	letrozole (2.5 mg) will be given from the second day of the cycle and for 5 days, gonadotropins will be given from the third day of the cycle and GnRH antagonist will be added from the six day of the cycle for controlled ovarian stimulation in IVF (interventional group). Participant will be exposed to mid luteal endometrial sample in the pretreatment cycle. couples will be asked to use condom in the pretreatment cycle.
gonadotropins and fixed GnRH antagonist (control group).	Gonadotropins	gonadotropins will be given from the third day of the cycle and GnRH antagonist will be added from the six day of the cycle for controlled ovarian stimulation in IVF(control group). Participant will be exposed to mid luteal endometrial sample in the pretreatment cycle. couples will be asked to use condom in the pretreatment cycle.
gonadotropins and fixed GnRH antagonist (control group).	endometrial sample in the pretreatment cycle	gonadotropins will be given from the third day of the cycle and GnRH antagonist will be added from the six day of the cycle for controlled ovarian stimulation in IVF(control group). Participant will be exposed to mid luteal endometrial sample in the pretreatment cycle. couples will be asked to use condom in the pretreatment cycle.

Primary Outcome Measures

Name	Time	Method
ongoing pregnancy rate.	12 weeks	Number of pregnant women with viable fetus at 12 weeks gestation per woman randomized

Secondary Outcome Measures

Name	Time	Method
miscarriage rate	20 weeks	Number of miscarriages per woman with positive pregnancy tests
multiple pregnancy rate	12 weeks	Number of multiple pregnancies per pregnant women with evident fetal pulsations
Correlation between mid-luteal gene expression of both αvβ3 integrin and leukemia inhibitory factor and the clinical outcomes of antagonist cycles with or without letrozole.	8 weeks	Correlation between mid-luteal gene expression of both αvβ3 integrin and leukemia inhibitory factor and the clinical outcomes of antagonist cycles with or without letrozole.
endometrial thickness at day of HCG administration	9-12 days from first day of menstruation when at least three growing follicle reaches above 18 mm	Thickness of endometrium
Rate of implantation	21 days after embryo transfer	Number of gestational sac recognized by ultrasound in uterus 3 weeks after embryo transfer
Rate of clinical pregnancy	5 weeks after embryo transfer	Number of gestational sacs with evident fetal pulsations per woman randomized
estrogen and progesterone levels during day of HCG,	9-12 days from first day of menstruation when at least three growing follicle reaches above 18 mm	estrogen and progesterone serum levels

Trial Locations

Locations (1)

Mansoura University; 🇪🇬 Mansoura, Egypt