Clinical trial NCT02710981: Sildenafil Vaginal Gel Co-treatment With Clomiphene Citrate in Infertile Women With Thin Endometrium
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Anovulation
Keywords: Sildenafil vaginal gel
endometrium
clomiphene
anovulation
Lead sponsor: Assiut University
Sponsor class: OTHER
First posted: 2016-03-17
Enrollment: 42
Sex: FEMALE
Minimum age (years): 20
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Endometrial Thickness
timeFrame: Day of HCG administration
Secondary outcomes:
measure: Uterine Blood Flow
timeFrame: Day of HCG administration
measure: Clinical Pregnancy Rate
timeFrame: At the end of a 28-day menstrual cycle.
Other outcomes:
Locations:
Study officials:
affiliation: Assiut University
name: Ahmed N. Fetih, M.D.
role: STUDY_DIRECTOR
References: