Extended Letrozole Regimen Versus Clomiphene Citrate for Superovulation in Patients With Unexplained Infertility Undergoing Intrauterine Insemination

Study Overview
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Brief Summary
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The aim of this randomized controlled trial is to compare the efficacy of extended letrozole regimen (2.5mg/day from cycle day 1 to 9) with clomiphene citrate (100 mg/day from cycle day 3 to 7) in women with unexplained infertility undergoing superovulation and intrauterine insemination .

Detailed Description
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Unexplained infertility is one of the most frequent infertility diagnoses encountered by the gynaecologists . Several studies reported that 10 to 20% of infertile couples have unexplained infertility . Superovulation and intrauterine insemination (IUI) is an effective treatment for couples with unexplained infertility . Superovulation increases the probability of pregnancy by increasing the number of oocytes suitable for fertilization or by correcting any subtle defect in ovulation . Furthermore, IUI increases the concentration of active motile sperms reaching the fallopian tube and overcomes male factors or cervical factors of infertility not detected by conventional tests . For more than four decades , clomiphene citrate has been the first line therapy used for induction of ovulation in women with anovulatory infertility and for superovulation in couples with unexplained infertility, mild endometriosis and mild male factor of infertility . Clomiphene citrate is cheap , orally administered , requires no frequent monitoring and associated with very low risk of high-order multiple gestation and severe ovarian hyperstimulation syndrome . However , clomiphene citrate causes long lasting depletion of estrogen receptors and therefore exerts antiestrogenic effect on estrogen target tissues as endocervical mucosa and endometrium .Several studies revealed the clomiphene citrate has a deleterious effect on cervical mucous quantity and quality and endometrial development resulting in endometrial thinning , luteal phase defect ,decreased uterine flow and implantation failure . During the past decade, letrozole (aromatase inhibitor approved by FDA for the treatment of postmenopausal women with breast cancer ) has been successfully used in induction of ovulation in anovulatory patients with polycystic ovary syndrome and in augmentation of ovulation in ovulatory women . In contrast to clomiphene citrate , letrozole is rapidly eliminated from the body and does not deplete estrogen receptors and therefore has no antiestrogenic effects on endometrium or endocervical mucosa . Several studies revealed that letrozole can be used as an alternative to clomiphene citrate for superovulation in patients with unexplained infertility . A metaanalysis of seven randomized controlled trials comparing aromatase inhibitors ( letrozole or anastrozole ) with clomiphene citrate in patients with unexplained infertility revealed that the pregnancy rate was comparable between both management options . The optimal dose and duration of letrozole administration for superovulation in patients with unexplained infertility is still not clear. In various studies reporting the use of letrozole for the superovulation , letrozole was administrated from cycle 3 to 7 with daily dose ranging from 2.5 to 7.5 mg .In a randomized controlled trial , AI-Fadhli et al reported that the pregnancy rate was significantly higher in patients with unexplained infertility treated with 5 mg compared to those treated with 2.5 mg . On the other hand, a randomized controlled trial comparing three doses of letrozole (2.5,5,7.5 mg/day)in the management of patients with unexplained infertility revealed that the pregnancy rates were comparable between the three groups . The aim of this randomized controlled trial is to compare the efficacy of extended letrozole regimen (2.5mg/day from cycle day 1 to 9) with clomiphene citrate (100 mg/day from cycle day 3 to 7) in women with unexplained infertility undergoing superovulation and intrauterine insemination .

Official Title
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Extended Letrozole Regimen Versus Clomiphene Citrate for Superovulation in Patients With Unexplained Infertility Undergoing Intrauterine Insemination

Conditions
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Infertility

Intervention / Treatment
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* Drug: Extended letrozole regimen
* Drug: Clomiphene citrate regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with unexplained infertility Age between 18 - 37 years Period of infertility > 1 year Patent Fallopian tubes detected by hysterosalpingography and/or laparoscopy Normal basal luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin concentrations Normal recent semen analysis (according to World Health Organization criteria) Exclusion Criteria: FSH> 10 IU/L Irregular menstrual cycles Polycystic ovary syndrome Endometriosis Endocrinologic disorders Systemic disease contraindicating pregnancy Previous IUI cycles liver or kidney diseases

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 37 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Extended letrozole regimen<br> | Drug: Extended letrozole regimen<br>* Letrozole (Femara; Novartis pharma AG, Basle, Switzerland) 2.5mg /day is administered from cycle day 1 to 9 . Human chorionic gonadotropin (Pregnyl; N.V. Organon, Oss, Holland) ( 10.000 IU/I.M ) is administered to trigger ovulation when at least one follicle measures more than 18mm in mean diameter .Intrauterine insemination is performed 36 - 40 hours after HCG injection . Starting from cycle day 9 , ultrasound scans are repeated daily to monitor follicle growth . Serum estradiol and endometrial thickness are measured on the day of HCG administration. Serum B-subunit HCG is measured 2 weeks after IUI to diagnose pregnancy .<br>* Other names: letrozole 2.5mg/day from cycle day 1 to 9;|
| Active Comparator: Clomiphene citrate regimen<br> | Drug: Clomiphene citrate regimen<br>* Clomiphene citrate(Clomid; Aventis pharma S.AE, Global Napi pharmaceuticals, Cairo, Egypt) 100 mg/day is administered from cycle day 3 to 7. Human chorionic gonadotropin (Pregnyl; N.V. Organon, Oss, Holland) ( 10.000 IU/I.M ) is administered to trigger ovulation when at least one follicle measures more than 18mm in mean diameter .Intrauterine insemination is performed 36 - 40 hours after HCG injection . Starting from cycle day 9 , ultrasound scans are repeated daily to monitor follicle growth . Serum estradiol and endometrial thickness are measured on the day of HCG administration. Serum B-subunit HCG is measured 2 weeks after IUI to diagnose pregnancy .<br>* Other names: Clomiphene citrate 100mg/day from cycle day 3 to 7;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical pregnancy rate | Presence of intrauterine gestational sac detected by transvaginal ultrasound | 5 weeks after intrauterine insemination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing Pregnancy Rate | Pregnancies continued beyond 20 weeks gestation | 18 weeks after intrauterine insemination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Letrozole ,Clomiphene citrate , IUI,unexplained infertility