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.
