Comparison between the effect of sildenafil and endometrial scratch injury on the outcome of (ICSI) cycle.

INTRODUCTION

The process of blastocyst implantation is complex; it involves interaction of variety of molecules. The receptivity of the endometrium affects blastocyst apposition and adhesion, as well as later trophoblast invasion. While steroid hormones (estrogen and progesterone) are known to control this process, the molecular basis of implantation is a major topic in the field. In vitro fertilization (IVF) cycles which lead in pregnancy, successful implantation is crucial and deemed the rate-limiting stage.

Various methods, such as endometrial scratch injury and sildenafil treatment, have been proposed in past years to enhance endometrial receptivity and implantation. To our knowledge, the literature does not agree about if endometrial injury raises the likelihood of pregnancy in women experiencing IVF cycles.  According to one study, conducting endometrial scratch injury before an ICSI cycle resulted in a higher rate of live births 99 ¹. In a yet another randomized controlled trial, researchers found no evidence that endometrial scratch injury has an effect on live birth rate in comparison to no intervention². The literature has also provided varying results when it comes to the exact timing of the endometrial scratch. The timing of endometrial injury in prior randomized control trials differed, with certain research conducting the injury among cycle days 4-7 ³, cycle days 16-23 ⁴, cycle days 21-26 ⁵, or even executing the procedure twice in the same cycle ⁶. Moreover, most research on endometrial injury undertakes the scratch during the luteal phase that prevents women from attempting pregnancy during the previous cycle. Despite improved research production over the last 15 years, there is a persistent lack of information about intervention.

Endometrial injury causes pain in the patient which can require a separate visit in addition to typical monitoring. The timing of endometrial scratch is examined in this research to see if there is a correlation between it and subsequent implantation.

Regarding the use of sildenafil citrate to enhance endometrium receptivity; there is growing evidence regarding the relation between uterine blood flow and endometrial response ⁷.

In women with a history of repeated miscarriages vaginal sildenafil was found to minimize peripheral natural killer cell (NK-cell) activity and enhance pregnancy rates. While the mechanism of sildenafil's effect on natural killer cell activity is unknown, increased uterine artery flow appears to have a significant impact on the endometrial NK-cell population ⁸.

In normal healthy populations, however, this drug has had adverse effects, including myocardial infarctions and strokes ^9,10.

The aim of this research was to compare the impacts of endometrial scratching and intravaginal sildenafil on endometrial receptivity in candidates with history of failed ICSI.

PATIENTS AND METHODS

From January 2017 to January 2019, a prospective randomized controlled study was performed in an IVF center. One hundred and fifty patients were enrolled in the research, the inclusion criteria being that they had at least one prior failed ICSI attempt and were good respondents with good quality embryos in those attempts. All patients with all kinds of fibroids or previous operations on the endometrium were removed from this research. Our sample was divided into 3 groups; Group A no intervention, Group B were endometrial scratch injury was done, and finally Group C with sildenafil therapy. In group B endometrial scratch injury occurred on the 21 day of the spontaneous cycle before ICSI-ET treatment using a pipelle endometrium sampler. Patients in group C received sildenafil citrate 25mg tablets 3 times daily intravaginally staring from the first day of FSH stimulation. Patients were randomly allocated to 3 groups during the IVF therapy cycle using a randomized block design to generate a random allocation sequence. Down regulation was started on the 21st day of the cycle preceding ovarian stimulation with injection of GnRH agonist daily, For pituitary down-regulation and endogenous gonadotropin depletion, patients were given 0.1 mg/day of the GnRH analogue (GnRH-a) buserelin acetate (Superfact),triptorelin acetate (Decapeptyl), or LeuproIide (Lupron). These patients were given 150—225 IU of hMG (Pergonal, Menogon, Menopure, or Gonal FI) daily to stimulate follicular growth after serum 17 E2 levels fell below 200 pmoI/L. The FSH/HMG dose was adjusted based on the patient's response.

On sonographic detection of at least two 18-mm leading follicles, 10,000 IU of hCG (Chorimon) were given to induce oocyte maturation, also the endometrium thickness is measured on this day.

And use a single lumen 17-gauge needle, oocytes were retrieved 32–36 hrs following hCG administration using guided vaginal sonography (Cook, Queensland, Australia). After fourteen days of luteal phase support, the patient was screened for pregnancy with beta-HCG titer, which was verified by transvaginal ultrasound after 10-15 days of pregnancy.

Statistical Methods:

Using the SPSS program statistical computer package version 12, the collected data was structured, tabulated, and statistically analyzed. The range, mean and standard deviations have been computed for the quantitative variables.

The student (t) test was used to statistically analyze the differences among the two means.

In order to test the relationship between the two variables, Pearson correlation coefficient (r) was determined. The number and percent distributions for categorical variables were determined. As a significance test, the Chi square test was used, and if it was found to be ineffective, the Fisher exact test was used.

     The significance level for interpreting the outcomes of significance tests was set at    p<0.05.

RESULTS

In our study we reviewed a total of 150 patients that were split among 3 groups. The base characteristics of our 3 research groups are shown in Table 1.There was no significant difference between the research groups regarding age, duration of infertility and body mass index (BMI). However, there was a significant difference among the groups regarding the endometrial thickness in both groups B, and C compared to the control group (P value 0.004 and 0.0037 respectively). A total of 23 patients (46%) in the control group achieved clinical pregnancy, while in group B 28 patients were pregnant (56%), and in group C 24 (48%) were pregnant.

Comparing the control group with group B, this revealed a significant difference regarding the 2 groups (p value 0.00401). The difference between the control group and group C, from the other hand, was not significant (p value 0.0671).

No statistically significant differences in the causes of infertility between groups.  In table 5. Comparison among the study groups regarding the number of previous IVF trials. In this aspect, there were no statistically significant differences among the groups.

Fig.1: Flowchart of participants in this trial.

DISCUSSION

Table 1: Patient’s characteristics and cycle related factors.

Table 2: Comparison of treatment cycle outcomes.

Table 3: Comparison between both groups as regard pregnancy rate.

Table 4: Comparison between groups with regard to cause of infertility.