Sildenafil Vaginal Gel Co-treatment With Clomiphene Citrate in Infertile Women With Thin Endometrium
Condition: Anovulation
MeSH terms: Anovulation
Study type: Interventional

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.
    

Intervention name(s): clomiphene citrate; Sildenafil vaginal gel
Intervention type(s): Drug; Drug
Intervention description(s): 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).; 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.
Other intervention name(s): clomid only; Viagra vaginal gel
Intervention MeSH terms: Sildenafil Citrate; Clomiphene; Enclomiphene; Zuclomiphene
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Sildenafil vaginal gel; endometrium; clomiphene; anovulation