Sildenafil Vaginal Gel Co-treatment With Clomiphene Citrate in Infertile Women With Thin Endometrium

Study Overview
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Brief Summary
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This is a prospective self controlled clinical trial. Women with clomiphene Citrate failure, and thin endometrium were recruited (N = 42). In their 6th (Clomiphene citrate only) cycle, women continued on Clomiphene citrate 100 mg/ day for 5 days, and had sonographic measurement of their endometrial thickness , and Doppler evaluation of their uterine arteries on the day of HCG administration. In 7th cycle, women (N = 36) were given usual dose of Clomiphene citrate supplemented with sildenafil vagina gel (5 gm, containing 50 mg sildenafil) twice daily from cycle day 8 till the day of HCG injection. Endometrial thickness and uterine artery Doppler were measured on the day of HCG administration.

Detailed Description
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Study design: This is a prospective self-controlled clinical trial. Study subjects: Investigators counseled and recruited 42 infertile women who had been diagnosed with anovulatory infertility, with normal baseline FSH, LH, and free testosterone levels, patent tubes on hysterosalpingography, and normal male semen analysis. By the time they were enrolled in the study, all women had already completed 5 ovulatory cycles of Clomiphene citrate induction (in a dose of 100 mg/ day in two divided doses starting from day 3 of the cycle for 5 days) but without conception (clomiphene citrate failure) with thin endometrium (<8mm) in at least 3 cycles. Ovulation was documented sonographically, and with day-21 serum progesterone exceeding 5 ng/ ml in all cases. Exclusion criteria: Women with major medical problems, male factor infertility, endocrine abnormalities such as hyperprolactinemia or abnormal thyroid functions, prior ovarian or adnexal surgery, or organic pelvic pathology were not included in the study. Intervention: Sixth cycle (Clomiphene citrate only): Enrolled cases were asked to continue with Clomiphene citrate induction ( at the same dose) for the 6th cycle. A gel base, without medicament (vehicle only), was applied vaginally in a dose of 5 gm twice per day, from cycle day 8 to the day of HCG administration ( when follicular diameter reached 18 mm). Endometrial thickness and Uterine artery Doppler assessment were done in the late proliferative phase ( Day of HCG injection). Seventh cycle ( Sildenafil vaginal gel and Clomiphene cycle): Those who didn't conceive on the sixth cycle (41 women) were asked to have an extra (7th) cycle in which they were prescribed the usual dose of Clomiphene citrate in addition to sildenafil vaginal gel. The sildenafil vaginal gel consists of sildenafil acetate as a medicament loaded on an in situ gelling system based on two polymers: Pluronic p-127, and Hydroxy Ethyl Cellulose. The dose was 5 g gel containing 50 mg sildenafil, applied vaginally twice daily from cycle day 8 to Day of HCG injection. The gel was prepared in collaboration with the department of pharmaceutics, faculty of Pharmacy, Assiut University. Sixty grams of gel were prepared in tubes and every patient was given 10 applicators like that used for administration of vaginal antimycotic creams to use them for applying the gel. Evaluation of the study end points: On day of HCG injection (main follicular diameter of 18 mm) in the 6th, and 7th cycles, women came for follow up and had transvaginal sonographic assessment of their endometrial thickness. Investigators have measured the maximal distance spanning endometrial- myometrial interphase on each endometrial stripe in a sagittal plane in the fundus of the uterus. In addition, Transvaginal Doppler examination was also done on the same visit to evaluate the pulsatility indices of both uterine arteries. When the leading follicle reached 18 mm in diameter, 5000 IU of HCG was prescribed for IM injection. Although pregnancy rate was not a primary outcome measure in the study, investigators detected pregnancy in 3 cases in the cohort of 36 cases of infertile women with clomiphene failure in which sildenafil gel was added as an adjuvant. Pregnancy was diagnosed with a B-HCG value above 100 mIU/ml, and confirmed later with ultrasound. Statistics: Data were analyzed using SPSS program ver. 17 using Student-t-test and Fisher's exact test for comparing data in the 6th and 7th cycles, as appropriate.

Official Title
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Effect of Sildenafil Vaginal Gel Co-treatment With Clomiphene Citrate on Endometrial Thickness in Infertile Women With Prior Clomiphene Citrate Failure Due to Thin Endometrium: a Prospective Self-controlled Clinical Trial

Conditions
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Anovulation

Intervention / Treatment
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* Drug: clomiphene citrate
* Drug: Sildenafil vaginal gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with clomiphene citrate failure (defined as at least prior 5 ovulatory cycles with clomiphene citrate, with no conception), persistently thin endometrium (less than 8 mm in at least 3 cycles). normal baseline FSH, LH, and free testosterone levels, patent tubes on hysterosalpingography, and normal male semen analysis Exclusion Criteria: Women with major medical problems, male factor infertility, endocrine abnormalities such as hyperprolactinemia or abnormal thyroid functions, prior ovarian or adnexal surgery, or organic pelvic pathology

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 40 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Clomiphene citrate only<br>women with prior 5 ovulatory cycles of Clomiphene citrate induction, but without conception (clomiphene citrate failure), with thin endometrium (<8mm) in at least 3 cycles. | Drug: clomiphene citrate<br>* Clomiphene citrate only arm: Patients received Clomiphene citrate induction ( (in a dose of 100 mg/ day in two divided doses starting from day 3 of the cycle for 5 days) for the 6th cycle. A gel base, without medicament (vehicle only), was applied vaginally in a dose of 5 gm twice per day, from cycle day 8 to the day of HCG injection. Sonographic assessment of endometrial thickness together with Uterine artery Doppler evaluation were done in the late proliferative phase ( Day of HCG injection).<br>* Other names: clomid only;|
| Experimental: Sildenafil vaginal gel and Clomiphene<br>Women who did not conceive on the Clomiphene citrate only cycle (41 women) were given Clomiphene citrate 100 mg/ day starting from day of the cycle for 5 days, with the addition to sildenafil vaginal gel 5 gm twice daily starting from day 8 of the cycle until day of HCG injection. | Drug: clomiphene citrate<br>* Clomiphene citrate only arm: Patients received Clomiphene citrate induction ( (in a dose of 100 mg/ day in two divided doses starting from day 3 of the cycle for 5 days) for the 6th cycle. A gel base, without medicament (vehicle only), was applied vaginally in a dose of 5 gm twice per day, from cycle day 8 to the day of HCG injection. Sonographic assessment of endometrial thickness together with Uterine artery Doppler evaluation were done in the late proliferative phase ( Day of HCG injection).<br>* Other names: clomid only;Drug: Sildenafil vaginal gel<br>* In addition to clomiphene citrate treatment as the previous group, women in the second arm were prescribed sildenafil vaginal gel in a dose of 5 g gel applied vaginally twice daily from cycle day 8 to the day of HCG injection. The sildenafil vaginal gel consists of sildenafil acetate as a medicament loaded on an in situ gelling system based on two polymers: Pluronic p-127, and Hydroxy Ethyl Cellulose.The gel was prepared in collaboration with the department of pharmaceutics, faculty of Pharmacy, Assiut University. Sixty grams of gel were prepared in tubes and every patient was given 10 applicators like that used for administration of vaginal antimycotic creams to use them for applying the gel.<br>* Other names: Viagra vaginal gel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endometrial Thickness | Transvaginal sonographic measurement of maximal distance spanning endometrial- myometrial interphase on each endometrial stripe in a sagittal plane in the fundus of the uterus | Day of HCG administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Uterine Blood Flow | Doppler ultrasound is used to measure the pulsatility index in both uterine arteries. Pulsatility index is a measure of the arterial resistance to blood flow. The higher the value of the pulsatility index, the more resistant the uterine arteries are, and hence the worst the outcome. | Day of HCG administration | 
| Clinical Pregnancy Rate | Identifying pregnancy through positive urinary HCG test plus sonographic detection of cardiac pulsations | At the end of a 28-day menstrual cycle. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sildenafil vaginal gel, endometrium, clomiphene, anovulation